Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen-Lysyl oxidase-like 2 (Loxl2)-is essential for ...interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.
Objectives We attempted to correlate echocardiographic analysis of diastolic function with changes of myocardial collagen in middle-aged patients with heart failure (HF) despite normal ejection ...fraction (EF). Background Increased collagen deposition may contribute to the deterioration of the left ventricular compliance and diastolic dysfunction in HF. Methods We investigated 41 patients (median age 50 years interquartile range: 41 to 57 years) with normal EF (median 62% interquartile range: 56% to 70%) whose endomyocardial biopsies were taken previously. Assessment of diastolic function was performed by mitral-flow and tissue Doppler measurements. Sirius red and immunohistologic staining was performed to determine collagen volume fraction (CVF) and cross-linking, collagen types I and III expression, and lysyl-oxidase (LOX) expression. Expression of collagen messenger ribonucleic acid was determined by real-time polymerase chain reaction. Results Twenty-six patients with HFNEF with diastolic dysfunction showed a significant increase in total collagen and collagen I expression compared with that of 15 controls. This was accompanied with enhanced collagen cross-linking and LOX overexpression in HFNEF. Among all flow Doppler, only deceleration time of E was associated with CVF (R = 0.43), whereas tissue Doppler parameters correlated with CVF, collagen I at the protein and mRNA levels (E' R = −0.58, −0.60, −0.45; E'/A' R = −0.32, −0.36, −0.31), and left ventricular filling index (E/E' R = 0.72, 0.68, 0.63), respectively. No correlation with collagen III was found. The degree of collagen cross-linking and LOX expression was related to E' (R = −0.55 and −0.60) and E/E' (R = 0.72 and 0.71), respectively, but not to flow Doppler. Collagen overexpression correlated with reduced exercise capacity. Conclusions Patients with HFNEF showed increased content of myocardial collagen type I, enhanced collagen cross-linking, and LOX expression, which were associated with impaired diastolic tissue Doppler parameters.
Abstract
Aims
Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). ...Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD).
Methods and results
Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = −0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-β)-dependent signalling. This enhanced TGF-β/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20).
Conclusions
Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-β signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-β-axis might be a promising therapeutic approach to reduce HFpEF.
Background: Tricuspid regurgitation is gaining importance due to its high morbidity and mortality. Especially in the elderly, novel technologies in percutaneous therapies have become valuable options ...due to the commonly present high surgical risk. Case presentation: We report a case of a 78-year-old female suffering from massive tricuspid regurgitation with repetitive right-sided heart failure hospitalizations. As the patient was very frail and deemed as high surgical risk, we used the TriClip® system to improve her symptomatic status. During diagnostic work-up, an additional membrane separating the right atrium, consistent with the definition of a cor triatriatum dexter, was found. Although increasing the complexity of the procedure, implantation of 3 clips with reduction of tricuspid regurgitation to a mild-to-moderate degree was achieved without any notable complications. The patient was discharged with ameliorated symptoms on the fourth postoperative day. Conclusions: Our case highlights the feasibility of percutaneous edge-to-edge tricuspid valve repair in an elderly woman with cor triatriatum dexter. Accurate echocardiographic visualization is an absolute requirement to gain access to the tricuspid valve without interacting with prevailing additional membranes.
Background
In recent years, new interventional therapies for tricuspid regurgitation (TR) demonstrated their effectiveness in reducing TR severity and improving symptoms. Currently, tricuspid ...transcatheter edge-to-edge repair (T-TEER) and percutaneous annuloplasty are the most widely used techniques in Europe. In this retrospective study, we compared procedural characteristics and learning curves of both TR devices in a real-world cohort.
Material and methods
Eligible patients with severe to torrential TR underwent either percutaneous annuloplasty or T-TEER as recommended by the local heart team. Patients with combined mitral and tricuspid interventions were excluded from the analysis. The study focused on procedural characteristics, TR reduction and learning curves.
Results
A total of 122 patients underwent either percutaneous annuloplasty (
n
= 64) or T-TEER (
n
= 58) with a technical and device success rate of 98% and 97%, respectively. Reasons for technical failure included right coronary artery (RCA) dissection prior to percutaneous annuloplasty, and two single leaflet device attachments (SLDA) during T-TEER implantation. The mean improvement of TR severity was 2.4 ± 0.8 degrees after T-TEER and 2.5 ± 0.8 after percutaneous annuloplasty. T-TEER procedures were shorter in terms of both procedure time and radiation exposure, while percutaneous annuloplasty, although taking longer, showed a significant reduction in procedure time over the course of the analysed period.
Conclusion
In summary, both interventional therapies reduce TR severity by approximately two degrees when used in the appropriate anatomy. The learning curve for annuloplasty group showed a significant decrease of procedure times.
Background
Transcatheter edge-to-edge repair (TEER) has developed from innovative technology to an established treatment strategy of mitral regurgitation (MR). The risk of iatrogenic mitral stenosis ...after TEER is, however, a critical factor in the conflict of interest between maximal reduction of MR and minimal impairment of left ventricular filling. We aim to investigate systematically the impact of device position on the post treatment hemodynamic outcome by involving the patient-specific segmentation of the diseased mitral valve.
Materials and methods
Transesophageal echocardiographic image data of ten patients with severe MR (age: 57 ± 8 years, 20% female) were segmented and virtually treated with TEER at three positions by using a position based dynamics approach. Pre- and post-interventional patient geometries were preprocessed for computational fluid dynamics (CFD) and simulated at peak-diastole with patient-specific blood flow boundary conditions. Simulations were performed with boundary conditions mimicking rest and stress. The simulation results were compared with clinical data acquired for a cohort of 21 symptomatic MR patients (age: 79 ± 6 years, 43% female) treated with TEER.
Results
Virtual TEER reduces the mitral valve area (MVA) from 7.5 ± 1.6 to 2.6 ± 0.6 cm
2
. Central device positioning resulted in a 14% smaller MVA than eccentric device positions. Furthermore, residual MVA is better predictable for central than for eccentric device positions (
R
2
= 0.81 vs.
R
2
= 0.49). The MVA reduction led to significantly higher maximal diastolic velocities (pre: 0.9 ± 0.2 m/s, post: 2.0 ± 0.5 m/s) and pressure gradients (pre: 1.5 ± 0.6 mmHg, post: 16.3 ± 9 mmHg) in spite of a mean flow rate reduction by 23% due to reduced MR after the treatment. On average, velocities were 12% and pressure gradients were 25% higher with devices in central compared to lateral or medial positions.
Conclusion
Virtual TEER treatment combined with CFD is a promising tool for predicting individual morphometric and hemodynamic outcomes. Such a tool can potentially be used to support clinical decision making, procedure planning, and risk estimation to prevent post-procedural iatrogenic mitral stenosis.
Background
Transcatheter annuloplasty is meant to target annular dilatation and is therefore mainly applied in functional tricuspid regurgitation (TR). Due to recent recognition of varying disease ...pathophysiology and differentiation of ventricular and atrial functional TR (VFTR and AFTR), comparative data regarding procedural success for both disease entities are required.
Methods
In this consecutively enrolled observational cohort study, 65 patients undergoing transcatheter annuloplasty with a Cardioband® device were divided into VFTR (
n
= 35, 53.8%) and AFTR (
n
= 30, 46.2%). Procedural success was assessed by comparing changes in annulus dilatation, vena contracta (VC) width, effective regurgitation orifice area (EROA), as well as reduction in TR severity.
Results
Overall, improvement of TR by at least two grades was achieved in 59 patients (90.8%), and improvement of TR by at least three grades was realised in 32 patients (49.2%). Residual TR of ≤2 was observed in 52 patients (80.0%). No significant differences in annulus diameter reduction VFTR: 11 mm (9–13) vs. AFTR: 12 mm (9–16),
p
= 0.210, VC reduction 12 mm (8–14) vs. 12 mm (7–14),
p
= 0.868, and EROA reduction 0.62 cm
2
(0.45–1.10) vs. 0.54 cm
2
(0.40–0.70),
p
= 0.204 were reported. Improvement by at least two grades 27 (90.0%) vs. 32 (91.4%),
p
= 1.0 and three grades 14 (46.7%) vs. 18 (51.4%),
p
= 0.805 was similar in VFTR and AFTR, respectively. No significant difference in the accomplishment of TR grade of ≤2 21 (70.0%) vs. 31 (88.6%),
p
= 0.118 was noted.
Conclusion
According to our results from a real-world scenario, transcatheter annuloplasty with the Cardioband® device may be applied in both VFTR and AFTR with evidence of significant procedural TR reduction.
BackgroundStroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke (AIS). We assessed whether enhanced diagnostic workup after AIS yields a higher rate of ...prespecified pathological findings compared with routine diagnostic care in-hospital.MethodsHospitalised patients with AIS were prospectively enrolled in the investigator-initiated observational HEart and BRain Interfaces in Acute Ischaemic Stroke (HEBRAS) study at the Charité, Berlin, Germany. Patients with AIS without known atrial fibrillation (AF) underwent cardiovascular MR imaging (CMR), MR-angiography of the aortic arch and prolonged Holter-ECG monitoring on top of routine diagnostic care.ResultsAmong 356 patients with AIS (mean age 66 years, 37.6% female), enhanced workup yielded a higher rate of prespecified pathological findings compared with routine care (17.7% vs 5.3%; p<0.001). Consequently, fewer patients were classified as cryptogenic after enhanced diagnostic workup (38.5% vs 45.5%, p<0.001). Routine care included echocardiography in 228 (64.0%) patients. CMR was successfully performed in 292 (82.0%) patients and revealed more often a prespecified pathological finding compared with routine echocardiography (16.1% vs 5.3%). Furthermore, study-related ECG monitoring (median duration 162 hours (IQR 98–210)) detected AF in 16 (4.5%) patients, while routine monitoring (median duration 51 hours (IQR 34–74)) detected AF in seven (2.0%) patients.ConclusionsEnhanced diagnostic workup revealed a higher rate of prespecified pathological findings in patients with AIS compared with routine diagnostic care and significantly reduced the proportion of patients with cryptogenic stroke.Trial registration number NCT02142413.
Background. The diagnosis of acute myocarditis (AMC) and inflammatory cardiomyopathy (DCMi) can be difficult. Speckle tracking echocardiography with accurate assessments of regional contractility ...could have an outstanding importance for the diagnosis. Methods and Results. N=25 patients with clinically diagnosed AMC who underwent endomyocardial biopsies (EMBs) were studied prospectively. Speckle tracking imaging was examined at the beginning and during a mean follow-up period of 6.2 months. In the acute phase patients had markedly decreased left ventricular (LV) systolic function (mean LV ejection fraction (LVEF) 40.4±10.3%). At follow-up in n=8 patients, inflammation persists, correlating with a significantly reduced fractional shortening (FS, 21.5±6.0%) in contrast to those without inflammation in EMB (FS 32.1±7.1%, P<0.05). All AMC patients showed a reduction in global systolic longitudinal strain (LS, −8.36±−3.47%) and strain rate (LSR, 0.53±0.29 1/s). At follow-up, LS and LRS were significantly lower in patients with inflammation, in contrast to patients without inflammation (−9.4±1.4 versus −16.8±2.0%, P<0.0001; 0.78±0.4 versus 1.3±0.3 1/s). LSR and LS correlate significantly with lymphocytic infiltrates (for CD3 r=0.7, P<0.0001, and LFA-1 r=0.8, P<0.0001). Conclusion. Speckle tracking echocardiography is a useful adjunctive assisting tool for evaluation over the course of intramyocardial inflammation in patients with AMC and DCMi.
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