Extracellular vesicles originate from diverse subcellular compartments and are released in the extracellular space. By transferring their cargoes into target cells and tissues, they now emerge as ...novel regulators of intercellular communication between adjacent and remote cells. Because vesicle composition and biological content are specific signatures of cellular activation and injury, their potential as diagnostic and prognostic biomarkers has raised significant interest in cardiovascular diseases. Characterization of circulating vesicles- or nonvesicles-bound nucleic acids represents a valuable tool for diagnosing and monitoring cardiovascular diseases, recently referred to as a liquid biopsy. Circulating extracellular vesicles offer a noninvasive and almost continuous access to circulating information on the disease state in epidemiological investigations. Finally, genetic engineering and cell-specific application of extracellular vesicles could display a novel therapeutic option for the treatment of cardiovascular diseases. In this review, we summarize the current knowledge about extracellular vesicles as diagnostic and prognostic biomarkers, as well as their potential applications for longitudinal epidemiological studies in cardiovascular diseases.
Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD). Both conditions are rising in incidence as well as prevalence, creating poor outcomes for ...patients and high healthcare costs. Recent data suggests CKD to be an independent risk factor for CVD. Accumulation of uremic toxins, chronic inflammation, and oxidative stress have been identified to act as CKD-specific alterations that increase cardiovascular risk. The association between CKD and cardiovascular mortality is markedly influenced through vascular alterations, in particular atherosclerosis and vascular calcification (VC). While numerous risk factors promote atherosclerosis by inducing endothelial dysfunction and its progress to vascular structural damage, CKD affects the medial layer of blood vessels primarily through VC. Ongoing research has identified VC to be a multifactorial, cell-mediated process in which numerous abnormalities like mineral dysregulation and especially hyperphosphatemia induce a phenotype switch of vascular smooth muscle cells to osteoblast-like cells. A combination of pro-calcifying stimuli and an impairment of inhibiting mechanisms like fetuin A and vitamin K-dependent proteins like matrix Gla protein and Gla-rich protein leads to mineralization of the extracellular matrix. In view of recent studies, intercellular communication pathways via extracellular vesicles and microRNAs represent key mechanisms in VC and thereby a promising field to a deeper understanding of the involved pathomechanisms. In this review, we provide an overview about pathophysiological mechanisms connecting CKD and CVD. Special emphasis is laid on vascular alterations and more recently discovered molecular pathways which present possible new therapeutic targets.
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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The transcatheter mitral valve interventions (TRAMI) registry was established in order to assess safety and efficacy of catheter-based mitral valve interventional techniques in Germany, and ...prospectively enrolled 828 MitraClip patients (median age 76 years, median log. EuroSCORE I 20.0%) between August 2010 and July 2013. We present the 1-year outcome in this MitraClip cohort-which is the largest published to date.
Seven forty-nine patients (90.5%) were available for 1-year follow-up and included in the following analyses. Mortality, major adverse cardiovascular event rates, and New York Heart Association (NYHA) classes were recorded. Predictors of 1-year mortality were identified by multivariate analysis using a Cox regression model with stepwise forward selection. The 1-year mortality was 20.3%. At 1 year, 63.3% of TRAMI patients pertained to NYHA functional classes I or II (compared with 11.0% at baseline), and self-rated health status (on EuroQuol visual analogue scale) also improved significantly by 10 points. Importantly, a significant proportion of patients regained the complete independence in self-care after MitraClip implantation (independence in 74.0 vs. 58.6% at baseline, P = 0.005). Predictors of 1-year mortality were NYHA class IV (hazard ratio, HR 1.62, P = 0.02), anaemia (HR 2.44, P = 0.02), previous aortic valve intervention (HR 2.12, P = 0.002), serum creatinine ≥1.5 mg/dL (HR 1.77, P = 0.002), peripheral artery disease (HR 2.12, P = 0.0003), left ventricular ejection fraction <30% (HR 1.58, P = 0.01), severe tricuspid regurgitation (HR 1.84, P = 0.003), and procedural failure (defined as operator-reported failure, conversion to surgery, failure of clip placement, or residual post-procedural severe mitral regurgitation) (HR 4.36, P < 0.0001).
Treatment of significant MR with MitraClip resulted in significant clinical improvements in a high proportion of TRAMI patients after 12 months. In the TRAMI cohort, the failure of procedural success exhibited the highest hazard ratio concerning the prediction of 1-year mortality.
Objectives The aim of this study was to provide a simple, reproducible, and point-of-care assessment of peri-prosthetic aortic regurgitation (periAR) during transcatheter aortic valve implantation ...(TAVI) and to decipher the impact of this peri-procedural parameter on outcome. Background Because periAR after TAVI might be associated with adverse outcome, precise quantification of periAR is of paramount importance but remains technically challenging. Methods The severity of periAR was prospectively evaluated in 146 patients treated with the Medtronic CoreValve (Minneapolis, Minnesota) prosthesis by echocardiography, angiography, and measurement of the aortic regurgitation (AR) index, which is calculated as ratio of the gradient between diastolic blood pressure (DBP) and left ventricular end-diastolic pressure (LVEDP) to systolic blood pressure (SBP): (DBP − LVEDP)/SBP × 100. Results After TAVI, 53 patients (36.3%) showed no signs of periAR and 71 patients (48.6%) showed only mild periAR, whereas 18 patients (12.3%) and 4 patients (2.7%) suffered from moderate and severe periAR, respectively. The AR index decreased stepwise from 31.7 ± 10.4 in patients without periAR, to 28.0 ± 8.5 with mild periAR, 19.6 ± 7.6 with moderate periAR, and 7.6 ± 2.6 with severe periAR (p < 0.001), respectively. Patients with AR index <25 had a significantly increased 1-year mortality risk compared with patients with AR index ≥25 (46.0% vs. 16.7%; p < 0.001). The AR index provided additional prognostic information beyond the echocardiographically assessed severity of periAR and independently predicted 1-year mortality (hazard ratio: 2.9, 95% confidence interval: 1.3 to 6.4; p = 0.009). Conclusions The assessment of the AR index allows a precise judgment of periAR, independently predicts 1-year mortality after TAVI, and provides additional prognostic information that is complementary to the echocardiographically assessed severity of periAR.
BACKGROUND—Repair of the endothelium after vascular injury is crucial for preserving endothelial integrity and preventing the development of vascular disease. The underlying mechanisms of endothelial ...cell repair are largely unknown. We sought to investigate whether endothelial microparticles (EMPs), released from apoptotic endothelial cells (ECs), influence EC repair.
METHODS AND RESULTS—Systemic treatment of mice with EMPs after electric denudation of the endothelium accelerated reendothelialization in vivo. In vitro experiments revealed that EMP uptake in ECs promotes EC migration and proliferation, both critical steps in endothelial repair. To dissect the underlying mechanisms, Taqman microRNA array was performed, and microRNA (miR)-126 was identified as the predominantly expressed miR in EMPs. The following experiments demonstrated that miR-126 was transported into recipient human coronary artery endothelial cells by EMPs and functionally regulated the target protein sprouty-related, EVH1 domain-containing protein 1 (SPRED1). Knockdown of miR-126 in EMPs abrogated EMP-mediated effects on human coronary artery endothelial cell migration and proliferation in vitro and reendothelialization in vivo. Interestingly, after simulating diabetic conditions, EMPs derived from glucose-treated ECs contained significantly lower amounts of miR-126 and showed reduced endothelial repair capacity in vitro and in vivo. Finally, expression analysis of miR-126 in circulating microparticles from 176 patients with stable coronary artery disease with and without diabetes mellitus revealed a significantly reduced miR-126 expression in circulating microparticles from diabetic patients.
CONCLUSIONS—Endothelial microparticles promote vascular endothelial repair by delivering functional miR-126 into recipient cells. In pathological hyperglycemic conditions, EMP-mediated miR-126–induced EC repair is altered.
Paravalvular aortic regurgitation (PAR) negatively affects the prognosis after transcatheter aortic valve replacement (TAVR) with dramatically increased morbidity and mortality in patients with more ...than mild PAR. Because transcatheter heart valves are implanted in a sutureless fashion using oversizing to anchor the prosthesis stent frame at the level of the virtual aortic annulus, stent frame underexpansion due to heavily calcified cusps, suboptimal placement of the prosthesis, and/or annulus-prosthesis-size mismatch due to malsizing can contribute to paravalvular leakage. In contrast to open heart surgery, TAVR does not offer the opportunity to measure the aortic annulus under direct vision during the procedure. Therefore, the dilemma before each TAVR procedure is the appropriate sizing of the dimensions of the aortic annulus and to choose not only the size but also the transcatheter heart valve type (self-expanding vs. balloon-expandable) that fits the given anatomy best. Because precise echocardiographic quantification of PAR in patients with TAVR remains challenging especially in the acute implantation situation, a multimodal approach for the evaluation of PAR with the use of hemodynamic measurements and imaging modalities is imperative to precisely quantify the severity of aortic regurgitation immediately after valve implantation and to identify patients who will benefit from corrective measures such as post-dilation or valve-in-valve implantation. Every measure has to be taken to prevent or reduce PAR to provide a satisfying long-term clinical outcome.
Abstract
Aims
The Cardioband™ (Edwards Lifesciences) is a transcatheter implant designed to reduce mitral annulus size and mitral regurgitation (MR) severity. We report the 1-year outcomes of ...consecutive patients who underwent the Cardioband procedure between 2013 and 2016.
Methods and results
Sixty patients with moderate or severe secondary MR (72 ± 7 years, 60% ischaemic origin) on guideline-recommended medical therapy were treated and analyzed at 11 European institutions. There were two in-hospital deaths (none device-related), one stroke, two coronary artery complications, and one tamponade. Anchor disengagement, observed in 10 patients (all but one in the first half of the population), resulted in device inefficacy in five patients and led to device modification half way through the study to mitigate this issue. Technical, device, and procedural successes, assessed based on Mitral Valve Academic Research Consortium (MVARC) criteria, were 97% (58/60), 72% (43/60), and 68% (41/60), respectively. At 1-year, overall survival, survival free of readmission for heart failure, and survival free of reintervention (performed in seven patients) were 87%, 66%, and 78%, respectively. In the overall population, MR grade at 12 months was moderate or less 61% and moderate or less in 95% of the 39 patients who underwent a transthoracic echocardiography at 1-year but worsened by at least one grade in 11 patients (22%). Functional status (79% vs. 14% in New York Heart Association Class I/II), quality of life (−19 points on the Minnesota Living with Heart Failure Questionnaire score), and exercise capacity (+58 m by 6MWT) improved significantly (all P < 0.01).
Conclusion
In this multicentre trial, the Cardioband mitral system demonstrated reasonable performance and safety. At 1 year, most patients had moderate or less MR and experienced significant functional improvements. A randomized controlled trial is underway to demonstrate the impact of Cardioband in patients on guideline-directed medical therapy.
Abstract
The right ventricular (RV)-pulmonary arterial (PA) coupling ratio relates the efficiency with which RV stroke work is transferred into the PA. Lower ratios indicate an inadequate RV contractile ...response to increased afterload.
This study sought to evaluate the prognostic significance of RV-PA coupling in patients with tricuspid regurgitation (TR) who were undergoing transcatheter tricuspid valve repair or replacement (TTVR).
The study investigators calculated RV-PA coupling ratios for patients enrolled in the global TriValve registry by dividing the tricuspid annular plane systolic excursion (TAPSE) by the PA systolic pressure (PASP) from transthoracic echocardiograms performed before the procedure and 30 days after the procedure. The primary endpoint was all-cause mortality at 1-year follow-up.
Among 444 patients analyzed, their mean age was 76.9 ± 9.1 years, and 53.8% of the patients were female. The median TAPSE/PASP ratio was 0.406 mm/mm Hg (interquartile range: 0.308-0.567 mm/mm Hg). Sixty-three patients died within 1 year of TTVR, 21 with a TAPSE/PASP ratio >0.406 and 42 with a TAPSE/PASP ratio ≤0.406. In multivariable Cox regression analysis, a TAPSE/PASP ratio >0.406 vs ≤0.406 was associated with a decreased risk of all-cause mortality (HR: 0.57; 95% CI: 0.35-0.93; P = 0.023). In 234 (52.7%) patients with echocardiograms 30 days after TTVR, a decline in RV-PA coupling was independently associated with reduced odds of all-cause mortality (odds ratio OR: 0.42; 95% CI: 0.19-0.93; P = 0.032). The magnitude of TR reduction after TTVR (≥1+ vs <1+; OR: 2.53; 95% CI: 1.06-6.03; P = 0.037) was independently associated with a reduction in post-TTVR RV-PA coupling.
RV-PA coupling is a powerful, independent predictor of all-cause mortality in patients with TR undergoing TTVR. These data suggest that the TAPSE/PASP ratio can inform patient selection and prognostication following TTVR.
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