The majority of patients with severe aortic stenosis (AS) planned for transcatheter aortic valve implantation (TAVI) are elective outpatients. During the COVID-19 pandemic, the time between the heart ...team's decision and TAVI increased due to limited healthcare resources. We therefore implemented telemedical approaches to identify AS patients at risk for clinical deterioration during the waiting time. The purpose of the prospective, randomized, controlled ResKriVer-TAVI study (DRKS00027842) is to investigate whether a digital concept of telemedical interventional management (TIM) in AS patients waiting for TAVI improves the clinical outcomes. In the present article, we report the study protocol of the ResKriVer-TAVI trial.
ResKriVer-TAVI will enroll AS patients planned for elective TAVI. Randomization to the TIM group or standard care will be made on the day of the heart team's decision. TIM will include a daily assessment of weight, blood pressure, a 2-channel electrocardiogram, peripheral capillary oxygen saturation, and a self-rated health status until admission for TAVI. TIM will allow optimization of medical therapy or an earlier admission for TAVI if needed. Standard care will not include any additional support for patients with AS. All patients of the TIM group will receive a rule-based TIM including standard operating procedures when a patient is crossing prespecified values of a vital sign.
The primary endpoint consists of days lost due to cardiovascular hospitalization and death of any cause within 180 days after the heart team's decision. Major secondary endpoints include all-cause mortality within 365 days, the number of telemedical interventions, and adherence to TIM. Follow-up visits will be conducted at admission for TAVI as well as 6 and 12 months after the heart team's decision.
ResKriVer-TAVI will be the first randomized, controlled trial investigating a telemedical approach before TAVI in patients with AS. We hypothesize that primary and secondary endpoints of AS patients with TIM will be superior to standard care. The study will serve to establish TIM in the clinical routine and to increase the resilience of TAVI centers in situations with limited healthcare resources.
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.
ABSTRACT
The insulin‐like peptide relaxin is a central hormone of pregnancy, but it also produces anti‐ fibrotic, myocardial, renal, central‐nervous, and vascular effects. Recently, two G protein‐ ...coupled receptors, LGR7 and LGR8, have been identified as relaxin receptors. Prompted by reports on immunoregulatory effects of relaxin, we investigated possible interactions with the human glucocorticoid receptor (GR). Relaxin blunted the endotoxin‐induced production of inflammatory cytokines (IL‐1, IL‐6, TNF‐α) by human macrophages—an effect that was suppressed by the GR antagonist RU‐486. In three different cell lines, relaxin induced GR activation, nuclear translocation, and DNA binding as assessed in GRE‐luciferase assays. Co‐ immunoprecipitation experiments revealed physical interaction of endogenous and exogenous relaxin with cytoplasmic and nuclear GR. Relaxin competed with GR agonists for GR binding, both in vivo, in whole‐cell assays, and in vitro, in fluorescence polarization assays. Relaxin was shown to up‐regulate GR protein expression as well as the number of functionally active GR sites. In LGR7/8‐free cells, the relaxin‐mediated activation of GR was preserved. In conclusion, relaxin acts as GR agonist—a pathway pivotal to its effects on cytokine secretion by human macrophages. These findings may deepen our understanding of relaxin’s abundant physiological actions, as well as our insights into general principles of hormone signaling.
Although infections are frequent in patients with pulmonary embolism (PE), its effect on adverse outcome risk remains unclear. We investigated the incidence and prognostic impact of infections ...requiring antibiotic treatment and of inflammatory biomarkers (C-reactive protein CRP and procalcitonin PCT) on in-hospital adverse outcomes (all-cause mortality or hemodynamic insufficiency) in 749 consecutive PE patients enrolled in a single-centre registry. Adverse outcomes occurred in 65 patients. Clinically relevant infections were observed in 46.3% of patients and there was an increased adverse outcome risk with an odds ratio (OR) of 3.12 (95% confidence interval CI 1.70-5.74), comparable to an increase in one risk class of the European Society of Cardiology (ESC) risk stratification algorithm (OR 3.45 95% CI 2.24-5.30). CRP > 124 mg/dL and PCT > 0.25 µg/L predicted patient outcome independent of other risk factors and were associated with respective ORs for an adverse outcome of 4.87 (95% CI 2.55-9.33) and 5.91 (95% CI 2.74-12.76). In conclusion, clinically relevant infections requiring antibiotic treatment were observed in almost half of patients with acute PE and carried a similar prognostic effect to an increase in one risk class of the ESC risk stratification algorithm. Furthermore, elevated levels of CRP and PCT seemed to be independent predictors of adverse outcome.
The objective of this study was to investigate whether immunoadsorption (IA) removes cardiodepressant antibodies from the plasma of patients with dilated cardiomyopathy (DCM), as well as to describe ...their effects on isolated rat cardiomyocytes.
Immunoadsorption induces early hemodynamic improvement in patients with DCM. The mechanisms for this improvement remain to be elucidated.
Patients with DCM (n = 11; left ventricular ejection fraction <30%, cardiac index CI <2.5 l/min per m2) were treated with IA on three consecutive days, with one IA session daily, by application of specific antibody columns directed against human immunoglobulin (Ig). Immunoadsorption was also conducted on 500 ml of blood taken from nine healthy donors (control subjects). After passage of plasma, the IA columns were regenerated. Column eluent (CE) was collected and dialyzed (100 kD). Confocal laser scanning microscopy was used to analyze the effects of CE on cell contraction and on Ca2+-dependent fluorescence in isolated, field-stimulated adult rat cardiomyocytes loaded with cell-permeable Fluo-3. Immunoprecipitation with different preparations of myocardial protein fractions was used for characterization of cardiotropic antibodies.
During IA, the IgG plasma level decreased from 10.7 ± 0.6 to 2.4 ± 0.1 g/l (mean ± SEM), and the CI increased from 2.2 ± 0.1 to 2.7 ± 0.2 l/min per m2(p < 0.01). The CE obtained from control subjects did not influence Ca2+transients or cell shortening of cardiomyocytes. In contrast, in patients with DCM, the CE collected during the first regeneration cycle of the first IA session caused an immediate and dose-related decrease of Ca2+transients (dilution 1:5; −22.7 ± 5.5%; p < 0.01) and cell shortening (dilution 1:5; −29.9 ± 6.0%, p < 0.01). Early hemodynamic improvement among the patients correlated with the cardiodepressant effect of CE on the isolated cardiomyocytes. Purification of CE by protein A adsorption indicated that the cardiodepressant substances are antibodies. Immunoprecipitation revealed that the eliminated antibodies are capable of binding to various myocardial proteins.
Cardiac autoantibodies play a functional role in DCM, and their removal may induce early hemodynamic improvement.
Six years previously, she had undergone a Ross procedure for severe aortic stenosis, with implantation of a decellularized porcine xenograft valve (Matrix P, Auto Tissue Berlin GmbH, Berlin, ...Germany). Because of the patient's poor general condition, the surgical risk was considered too high, and a catheter approach was performed (B-F,Online Video 2).
Introduction There is a lack of real-world data directly comparing different valve prostheses for transaortic valve replacement (TAVR). We aimed to compare early clinical outcomes at 30-days between ...the self-expandable Portico valve (Abbott) with the balloon-expandable Edwards Sapien 3 valve (Edwards Lifesciences) (ES3). Methods Out of 1,901 patients undergoing TAVR between January 2018 and December 2021, all patients who received either Portico valve or ES3 valve via transfemoral TAVR were matched using nearest-neighbor (1:1) propensity scoring. Primary endpoints were single safety endpoints and early safety composite endpoints defined by Valve Academic Research Consortium-2 (VARC-2) criteria. The secondary endpoint was to analyze risk predictors for new permanent pacemaker (PPM) implantation in TAVR. Results Out of 661 complete cases, a total of 434 patients were successfully matched based on age, sex, Euro Score II and STS-score. In the matched cohort, 217 received either a Portico or valve and 217 received an ES3 valve. The VARC-2 early safety composite scores indicated a significantly greater overall 30-day safety risk in the Portico group at 9.2% ( n = 20) compared to 3.7% ( n = 8) in the ES3 group ( p = 0.032). The requirement for new permanent pacemaker (PPM) implantation was also higher in the Portico group, at 21.2% ( n = 46) vs. 13.4% ( n = 29) in the ES3 group ( p = 0.042). 30-day mortality was higher was 3.7% ( n = 8) in Portico group compared to 0.9% in ES3 group ( p = 0.11). Furthermore, implantation of the Portico valve was identified as a significant risk predictor for new PPM implantation, alongside higher age, preprocedural atrioventricular block (AVB) and longer total procedure duration. Conclusion This study shows significantly higher rates of early clinical complications for Portico valve prostheses compared to ES3. These findings should be especially taken into consideration when selecting valve prosthesis for high-risk patients.
Immunoadsorption (IA) and subsequent immunoglobulin (Ig) G substitution represent an additional therapeutic approach in dilated cardiomyopathy (DCM). It remains to be elucidated whether this ...treatment modulates myocardial inflammation, which is possibly a causal factor of ventricular dysfunction.
From 25 DCM patients (EF <30%), 12 patients were randomized for IA therapy and subsequent IgG substitution at 1-month intervals until month 3. Before (<7 days) and after IA therapy, right ventricular biopsies were obtained from all patients. Biopsies were also obtained at intervals of 3 months from 13 patients without IA/IgG treatment (controls). IA/IgG treatment induced improvement in left ventricular ejection fraction from 21.3+/-1.7% (+/-SEM) to 27.0+/-1.3% (P<0.01 versus baseline/controls) and reduction of the beta-receptor autoantibody serum levels (P<0.01 versus baseline/controls). The number of CD3 cells decreased from 5.7+/-0.8 to 2.9+/-0.5 cells/mm(2) (P<0.01 versus baseline/controls). This decline was paralleled by a decrease in CD4 (P<0.01 versus baseline/controls) and CD8 (P<0.05 versus baseline/controls) lymphocytes. The number of leukocyte common antigen-positive cells (leukocytes) was reduced from 20.0+/-3.2 to 9.9+/-2.8 cells/mm(2) (P<0.01 versus baseline/P<0.05 versus controls). HLA class II expression decreased from 2.1+/-0.7% to 1.1+/-0.4% (P<0.05 versus controls/baseline). The number of immunopositive cells and the expression of HLA class II in controls remained stable. In both groups, the degree of fibrosis remained unchanged.
IA and subsequent IgG substitution mitigate myocardial inflammation in DCM.
We recently demonstrated that non-toxic inhibition of the proteasome upregulates antioxidative enzymes and leads to an adaptive transcriptional pattern in endothelial cells. We therefore hypothesized ...that proteasome inhibition could prevent experimentally-induced endothelial dysfunction. As there are conflicting data about the effects of proteasome inhibition on endothelial function, we investigated whether proteasome inhibition could prevent experimentally-induced endothelial dysfunction.
Endothelial dysfunction in isolated rat aortic rings was induced by incubation of rings with TNFα for 48 h. To study the effects of the inhibition of the proteasome, selected rings were co-treated with proteasome inhibitors. Vasorelaxation and expression of genes involved in endothelial function were evaluated.
Incubation of rat aortic rings with TNFα for 48 h led to significant dose-dependent reduction of acetylcholine-induced vasorelaxation. Co-incubation with TNFα and the proteasome inhibitor MG132 resulted in dose-dependent improvement of endothelium-dependent vasorelaxation in comparison to rings treated with TNFα alone. Levels of eNOS mRNA and protein were reduced despite improved vascular function after treatment with MG132. MG132 markedly suppressed mRNA levels of NADPH oxidase subunits and increased SOD1 expression. Superoxide production was reduced in rings incubated with MG132 in comparison to controls. TNFα-induced upregulation of the potent vasoconstrictor endothelin was abolished by MG132.
Proteasome inhibition prevents TNFα-induced vascular dysfunction by reduction of superoxide production and suppression of endothelin levels. The balance between vasoconstriction and vasodilatation is shifted in favour of endothelium-dependent vasodilation.
OBJECTIVES
The objective of our study was to assess the hemodynamic effects of immunoadsorption (IA) and subsequent immunoglobulin G (IgG) substitution in comparison with the effects of conventional ...medical treatment in patients with dilated cardiomyopathy (DCM).
BACKGROUND
Various circulating cardiac autoantibodies have been detected among patients suffering from DCM. These antibodies are extractable by IA.
METHODS
Patients with DCM (n = 18, New York Heart Association III–IV, left ventricular ejection fraction <30%) and who were on stable medication participated in the study. Hemodynamic measurements were performed using a Swan-Ganz thermodilution catheter. The patients were randomly assigned either to the treatment group with IA and subsequent IgG substitution (IA/IgG group, n = 9) or to the control group without IA/IgG (n = 9). In the IA/IgG group, the patients were initially treated in one IA session daily on three consecutive days. After the final IA session, 0.5 g/kg of polyclonal IgG was substituted. At one-month intervals, IA was then repeated for three further courses with one IA session daily on two consecutive days, until the third month.
RESULTS
After the first IA course and IgG substitution, cardiac index (CI) increased from 2.1 (±0.1) to 2.8 (±0.1) L/min/m2 (p < 0.01) and stroke volume index (SVI) increased from 27.8 (±2.3) to 36.2 (±2.5) ml/m2 (p < 0.01). Systemic vascular resistance (SVR) decreased from 1,428 (±74) to 997 (±55) dyne·s·cm−5 (p < 0.01). The improvement in CI, SVI and SVR persisted after three months. In contrast, hemodynamics did not change throughout the three months in the control group.
CONCLUSIONS
Immunoadsorption and subsequent IgG substitution improves cardiovascular function in DCM.
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