Tricuspid regurgitation is a prevalent disease associated with high morbidity and mortality, with few treatment options. The aim of the TRILUMINATE trial is to evaluate the safety and effectiveness ...of TriClip, a minimally invasive transcatheter tricuspid valve repair system, for reducing tricuspid regurgitation.
The TRILUMINATE trial is a prospective, multicentre, single-arm study in 21 sites in Europe and the USA. Patients with moderate or greater triscuspid regurgitation, New York Heart Association class II or higher, and who were adequately treated per applicable standards were eligible for enrolment. Patients were excluded if they had systolic pulmonary artery pressure of more than 60 mm Hg, a previous tricuspid valve procedure, or a cardiovascular implantable electronic device that would inhibit TriClip placement. Participants were treated using a clip-based edge-to-edge repair technique with the TriClip tricuspid valve repair system. Tricuspid regurgitation was graded using a five-class grading scheme (mild, moderate, severe, massive, and torrential) that expanded on the standard American Society of Echocardiography grading scheme. The primary efficacy endpoint was a reduction in tricuspid regurgitation severity by at least one grade at 30 days post procedure, with a performance goal of 35%, analysed in all patients who had an attempted tricuspid valve repair procedure upon femoral vein puncture. The primary safety endpoint was a composite of major adverse events at 6 months, with a performance goal of 39%. Patients were excluded from the primary safety analysis if they did not reach 6-month follow-up and did not have a major adverse event during previous follow-ups. The trial has completed enrolment and follow-up is ongoing; it is registered with ClinicalTrials.gov, number NCT03227757.
Between Aug 1, 2017, and Nov 29, 2018, 85 patients (mean age 77·8 years SD 7·9; 56 66% women) were enrolled and underwent successful TriClip implantation. Tricuspid regurgitation severity was reduced by at least one grade at 30 days in 71 (86%) of 83 patients who had available echocardiogram data and imaging. The one-sided lower 97·5% confidence limit was 76%, which was greater than the prespecified performance goal of 35% (p<0·0001). One patient withdrew before 6-month follow-up without having had a major adverse event and was excluded from analysis of the primary safety endpoint. At 6 months, five (6%) of 84 patients experienced a major adverse event, which was less than the prespecified performance goal of 39% (p<0·0001). Single leaflet attachment occurred in five (7%) of 72 patients. No periprocedural deaths, conversions to surgery, device embolisations, or strokes occurred. At 6 months, all-cause mortality had occurred in four (5%) of 84 patients.
The TriClip system appears to be safe and effective at reducing tricuspid regurgitation by at least one grade. This reduction could translate to significant clinical improvement at 6 months post procedure.
Abbott.
Tricuspid regurgitation (TR) is a frequent disease with a progressive increase in mortality as disease severity increases. Transcatheter therapies for treatment of TR may offer a safe and effective ...alternative to surgery in this high-risk population.
The purpose of this report was to study the 1-year outcomes with the TriClip transcatheter tricuspid valve repair system, including repair durability, clinical benefit and safety.
The TRILUMINATE trial (n = 85) is an international, prospective, single arm, multicenter study investigating safety and performance of the TriClip Tricuspid Valve Repair System in patients with moderate or greater TR. Echocardiographic assessment was performed by a core laboratory.
At 1 year, TR was reduced to moderate or less in 71% of subjects compared with 8% at baseline (p < 0.0001). Patients experienced significant clinical improvements in New York Heart Association (NYHA) functional class I/II (31% to 83%, p < 0.0001), 6-minute walk test (272.3 ± 15.6 to 303.2 ± 15.6 meters, p = 0.0023) and Kansas City Cardiomyopathy Questionnaire (KCCQ) score (improvement of 20 ± 2.61 points, p < 0.0001). Significant reverse right ventricular remodeling was observed in terms of size and function. The overall major adverse event rate and all-cause mortality were both 7.1% at 1 year.
Transcatheter tricuspid valve repair using the TriClip device was found to be safe and effective in patients with moderate or greater TR. The repair itself was durable at reducing TR at 1 year and was associated with a sustained and marked clinical benefit with low mortality after 1 year in a fragile population that was at high surgical risk. (TRILUMINATE Study With Abbott Transcatheter Clip Repair System in Patients With Moderate or Greater TR; NCT03227757)
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Abstract Background Low flow (LF) can occur with reduced (classic) or preserved (paradoxical) left ventricular ejection fraction (LVEF). Objectives The objective of this study was to compare outcomes ...of patients with low ejection fraction (LEF), paradoxical low flow (PLF), and normal flow (NF) after aortic valve replacement (AVR). Methods We examined 1,154 patients with severe aortic stenosis (AS) who underwent AVR with or without coronary artery bypass grafting. Results Among these patients, 206 (18%) had LEF as defined by LVEF of <50%; 319 (28%) had PLF as defined by LVEF of ≥50% but stroke volume indexed to body surface area (SVi) of ≤35 ml ∙ m−2 ; and 629 (54%) had NF, as defined by LVEF of ≥50% and SVi of >35 ml ∙ m2 . Aortic valve area was lower in low flow/LVEF groups (LEF: 0.71 ± 0.20 cm2 and PLF: 0.65 ± 0.23 cm2 vs. NF: 0.77 ± 0.18 cm2 ; p < 0.001). The 30-day mortality was higher (p < 0.001) in LEF and PLF groups than in the NF group (6.3% and 6.3% vs. 1.8%, respectively). SVi and PLF group were independent predictors of operative mortality (odds ratio OR: 1.18, p < 0.05; and OR: 2.97, p = 0.004; respectively). At 5 years after AVR, overall survival was 72 ± 4% in LEF group, 81 ± 2% in PLF group, and 85 ± 2% in NF group (p < 0.0001). Conclusions Patients with LEF or PLF AS have a higher operative risk, but pre-operative risk score accounted only for LEF and lower LVEF. Patients with LEF had the worst survival outcome, whereas patients with PLF and normal flow had similar survival rates after AVR. As a major predictor of perioperative mortality, SVi should be integrated in AS patients’ pre-operative evaluation.
Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in ...PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH.
We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription-polymerase chain reaction; P<0.01) and capillary density (CD31(+) immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals.
RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH.
Mendelian randomization studies have highlighted that lipoprotein(a) Lp(a) was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids with a high content in ...lysophosphatidylcholine. Autotaxin (ATX) transforms lysophosphatidylcholine into lysophosphatidic acid. We hypothesized that ATX-lysophosphatidic acid could promote inflammation/mineralization of the aortic valve.
We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches, we have also investigated the role of ATX-lysophosphatidic acid in the mineralization of isolated valve interstitial cells and in a mouse model of CAVD. Enzyme-specific ATX activity was elevated by 60% in mineralized aortic valves in comparison with control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which colocalized with oxidized phospholipids and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that valve interstitial cells also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promotes the mineralization of the aortic valve through a nuclear factor κB/interleukin 6/bone morphogenetic protein pathway. In LDLR(-/-)/ApoB(100/100)/IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD.
ATX is transported in the aortic valve by Lp(a) and is also secreted by valve interstitial cells. ATX-lysophosphatidic acid promotes inflammation and mineralization of the aortic valve and thus could represent a novel therapeutic target in CAVD.
In the American College of Cardiology/American Heart Association guidelines, patients are considered to have true-severe stenosis when the mean gradient (MG) is ≥40 mm Hg with an aortic valve area ...(AVA) ≤1 cm2 during dobutamine stress echocardiography (DSE). However, these criteria have not been previously validated.
The aim of this study was to assess the value of these criteria to predict the presence of true-severe AS and the occurrence of death in patients with low-flow, low-gradient aortic stenosis (LF-LG AS).
One hundred eighty-six patients with low left ventricular ejection fraction (LVEF) LF-LG AS were prospectively recruited and underwent DSE, with measurement of the MG, AVA, and the projected AVA (AVAProj), which is an estimate of the AVA at a standardized normal flow rate. Severity of AS was independently corroborated by macroscopic evaluation of the valve at the time of valve replacement in 54 patients, by measurement of the aortic valve calcium by computed tomography in 25 patients, and by both methods in 8 patients. According to these assessments, 50 of 87 (57%) patients in the study cohort had true-severe stenosis.
Peak stress MG ≥40 mm Hg, peak stress AVA ≤1 cm2, and the combination of peak stress MG ≥40 mm Hg and peak stress AVA ≤1 cm2 correctly classified AS severity in 48%, 60%, and 47% of patients, respectively, whereas AVAProj ≤1 cm2 was better than all the previous markers (p < 0.007), with 70% correct classification. Among the subset of 88 patients managed conservatively (47% of the cohort), 52 died during a follow-up of 2.8 ± 2.5 years. After adjustment for age, sex, functional capacity, chronic kidney failure, and peak stress LVEF, peak stress MG and AVA were not predictors of mortality in this subset. In contrast, AVAProj ≤1 cm2 was a strong predictor of mortality under medical management (hazard ratio: 3.65; p = 0.0003).
In patients with low LVEF LF-LG AS, the DSE criteria of a peak stress MG ≥40 mm Hg, or the composite of a peak stress MG ≥40 mm Hg and a peak stress AVA ≤1 cm2 proposed in the guidelines to identify true-severe AS and recommend valve replacement, have limited value to predict actual stenosis severity and outcomes. In contrast, AVAProj better distinguishes true-severe AS from pseudo-severe AS and is strongly associated with mortality in patients under conservative management. (Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis TOPAS; NCT01835028)
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Abstract Background Residual aortic regurgitation (AR) following transcatheter aortic valve replacement (TAVR) is associated with greater mortality; yet, determining AR severity post-TAVR using ...Doppler echocardiography remains challenging. Cardiovascular magnetic resonance (CMR) is purported as a more accurate means of quantifying AR; however, no data exist regarding the prognostic value of AR as assessed by CMR post-TAVR. Objectives This study sought to evaluate the effect of AR assessed with CMR on clinical outcomes post-TAVR. Methods We included 135 patients from 3 centers. AR was quantified using regurgitant fraction (RF) measured by phase-contrast velocity mapping CMR at a median of 40 days post-TAVR, and using Doppler echocardiography at a median of 6 days post-TAVR. Median follow-up was 26 months. Clinical outcomes included mortality and rehospitalization for heart failure. Results Moderate-severe AR occurred in 17.1% and 12.8% of patients as measured by echocardiography and CMR, respectively. Higher RF post-TAVR was associated with increased mortality (hazard ratio: 1.18 for each 5% increase in RF 95% confidence interval: 1.08 to 1.30; p < 0.001) and the combined endpoint of mortality and rehospitalization for heart failure (hazard ratio: 1.19 for each 5% increase in RF; 95% confidence interval: 1.15 to 1.23; p < 0.001). Prediction models yielded significant incremental predictive value; CMR performed a median of 40 days post-TAVR had a greater association with post-TAVR clinical events compared with early echocardiography (p < 0.01). RF ≥30% best predicted poorer clinical outcomes (p < 0.001 for either mortality or the combined endpoint of mortality and heart failure rehospitalization). Conclusions Worse CMR-quantified AR was associated with increased mortality and poorer clinical outcomes following TAVR. Quantifying AR with CMR may identify patients with AR who could benefit from additional treatment measures.
The transthoracic echocardiographic (TTE) evaluation of the severity of residual aortic regurgitation (AR) following transcatheter aortic valve implantation (TAVI) has been controversial and lacks ...validation.
This study sought to compare TTE and cardiac magnetic resonance (CMR) for assessment of AR in patients undergoing TAVI with a balloon-expandable valve.
TTE and CMR exams were performed pre-TAVI in 50 patients and were repeated postprocedure in 42 patients. All imaging data were analysed in centralised core laboratories.
The severity of native AR as determined by multiparametric TTE approach correlated well with the regurgitant volume and regurgitant fraction determined by CMR prior to TAVI (Rs=0.79 and 0.80, respectively; p<0.001 for both). However, after TAVI, the correlation between the prosthetic AR severity assessed by TTE and regurgitant volume and fraction measured by CMR was only modest (Rs=0.59 and 0.59, respectively; p<0.001 for both), with an underestimation of AR severity by TTE in 61.9% of patients (1 grade in 59.5%). The TTE jet diameter in parasternal view and the multiparametric approach (Rs=0.62 and 0.59, respectively; both with p<0.001) showed the best correlation with CMR regurgitant fraction post-TAVI. The circumferential extent of prosthetic paravalvular regurgitation showed a poor correlation with CMR regurgitant volume and fraction (Rs=0.32, p=0.084; Rs=0.36, p=0.054, respectively).
The severity of AR following TAVI with a balloon-expandable valve was underestimated by echocardiography as compared with CMR. The jet diameter, but not the circumferential extent of the leaks, and the multiparametric echocardiography integrative approach best correlated with CMR findings. These results provide important insight into the evaluation of AR severity post-TAVI.
The SAPIEN 3 valve (S3V) is a new-generation transcatheter valve with enhanced anti-paravalvular leak properties, but no data comparing with earlier transcatheter valve systems are available. We ...aimed to compare the hemodynamic performance of the S3V and the SAPIEN XT valve (SXTV) in a case-matched study with echo core laboratory analysis. A total of 27 patients who underwent transcatheter aortic valve replacement (TAVR) with the S3V were matched for prosthesis size (26 mm), aortic annulus area, and mean diameter measured by computed tomography, left ventricular ejection fraction, body surface area, and body mass index with 50 patients treated with the SXTV. The prosthesis size was determined by oversizing of 1% to 15% of annulus area. Doppler echocardiographic images collected at baseline and 1-month follow-up were analyzed in a central echocardiography core laboratory. The need for postdilation was higher in the SXTV group (20% vs 4%, p = 0.047), and mean residual gradient and effective orifice area were similar in both groups (p >0.05). The incidence of paravalvular aortic regurgitation was greater with the SXTV (≥mild: 42%, moderate: 8%) than with the S3V (≥mild: 7%, moderate: 0%; p = 0.002 for ≥mild vs SXTV). The implantation of an S3V was the only factor associated with trace or no paravalvular leak after TAVR (p = 0.007). In conclusion, TAVR with the S3V was associated with a very low rate of paravalvular leaks and need for balloon postdilation, much lower than that observed with the earlier generation of balloon-expandable valve (SXTV). The confirmation of these results in a larger cohort of patients will represent a major step forward in using transcatheter valves for the treatment of aortic stenosis.
Background No randomized comparison of early (ie, ≤3 months) aortic valve replacement (AVR) versus conservative management or of transcatheter AVR (TAVR) versus surgical AVR has been conducted in ...patients with low-flow, low-gradient (LFLG) aortic stenosis (AS). Methods and Results A total of 481 consecutive patients (75±10 years; 71% men) with LFLG AS (aortic valve area ≤0.6 cm
/m
and mean gradient <40 mm Hg), 72% with classic LFLG and 28% with paradoxical LFLG, were prospectively recruited in the multicenter TOPAS (True or Pseudo Severe Aortic Stenosis) study. True-severe AS or pseudo-severe AS was adjudicated by flow-independent criteria. During follow-up (median IQR 36 11-60 months), 220 patients died. Using inverse probability of treatment weighting to address the bias of nonrandom treatment assignment, early AVR (n=272) was associated with a major overall survival benefit (hazard ratio HR, 0.34 95% CI, 0.24-0.50;
<0.001). This benefit was observed in patients with true-severe AS but also with pseudo-severe AS (HR, 0.38 95% CI, 0.18-0.81;
=0.01), and in classic (HR, 0.33 95% CI, 0.22-0.49;
<0.001) and paradoxical LFLG AS (HR, 0.42 95% CI, 0.20-0.92;
=0.03). Compared with conservative management in the conventional multivariate model, trans femoral TAVR was associated with the best survival (HR, 0.23 95% CI, 0.12-0.43;
<0.001), followed by surgical AVR (HR, 0.36 95% CI, 0.23-0.56;
<0.001) and alternative-access TAVR (HR, 0.51 95% CI, 0.31-0.82;
=0.007). In the inverse probability of treatment weighting model, trans femoral TAVR appeared to be superior to surgical AVR (HR 95% CI 0.28 0.11-0.72;
=0.008) with regard to survival. Conclusions In this large prospective observational study of LFLG AS, early AVR appeared to confer a major survival benefit in both classic and paradoxical LFLG AS. This benefit seems to extend to the subgroup with pseudo-severe AS. Our findings suggest that TAVR using femoral access might be the best strategy in these patients. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01835028.
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