Remote Ischemic Preconditioning Neither Improves Survival nor Reduces Myocardial or Kidney Injury in Patients Undergoing Transcatheter Aortic Valve Implantation (TAVI)

BACKGROUND: Peri-interventional myocardial injury occurs frequently during transcatheter aortic valve implantation (TAVI). We assessed the effect of remote ischemic preconditioning (RIPC) on myocardial injury, acute kidney injury (AKIN) and 6-month mortality in patients undergoing TAVI. METHODS: We performed a prospective single-center controlled trial. Sixty-six patients treated with RIPC prior to TAVI were enrolled in the study and were matched to a control group by propensity-score. RIPC was applied to the upper extremity using a conventional tourniquet. Myocardial injury was assessed using high-sensitive troponin-T (hsTnT), and kidney injury was assessed using serum creatinine levels. Data were compared with the Wilcoxon-Rank and McNemar tests. Mortality was analysed with the log-rank test. RESULTS: TAVI led to a significant rise of hsTnT across all patients (p < 0.001). No significant inter-group difference in maximum troponin release or areas-under-the-curve was detected. Medtronic CoreValve and Edwards Sapien valves showed similar peri-interventional troponin kinetics and patients receiving neither valve did benefit from RIPC. AKIN occurred in one RIPC patient and four non-RIPC patients (p = 0.250). No significant difference in 6-month mortality was observed. No adverse events related to RIPC were recorded. CONCLUSION: Our data do not show a beneficial role of RIPC in TAVI patients for cardio- or renoprotection, or improved survival

Simple periprocedural precautions to reduce Doppler microembolic signals during AF ablation

Background!#!Doppler microembolic signals (MES) occur during atrial fibrillation ablation despite of permanent flushed transseptal sheaths, frequent controls of periprocedural coagulation status and the use of irrigated ablation catheters PURPOSE: To investigate the number and type of MES depending on the procedure time, prespecified procedure steps, the activated clotting time (ACT) during the ablation procedure and the catheter contact force.!##!Methods!#!In a prospective trial, 53 consecutive atrial fibrillation patients underwent pulmonary vein isolation by super-irrigated 'point-by-point' ablation. All patients underwent a periinterventional, continuous transcranial Doppler examination (TCD) of the bilateral middle cerebral arteries during the complete ablation procedure.!##!Results!#!An average of 686±226 microembolic signals were detected by permanent transcranial Doppler. Thereby, 569±208 signals were differentiated as gaseous and 117±31 as solid MES. The number of MES with regard to defined procedure steps were as follows: gaseous: [transseptal puncture, 26 ± 28; sheath flushing, 24±12; catheter change, 21±11; angiography, 101±28; mapping, 9±9; ablation, 439±192; protamine administration, 0±0]; solid: [transseptal puncture, 8±8; sheath flushing, 9±5; catheter replacement, 6±6; angiography, not measurable; mapping, 2±5; ablation, 41±22; protamine administration, 0±0]. Significantly less MES occurred with shorter procedure time, higher ACT and the use of tissue contact force monitoring.!##!Conclusion!#!The current study demonstrates that during atrial fibrillation ablation using irrigated, 'point-by-point' RF ablation, masses of microembolic signals are detected in transcranial ultrasound especially in the period of RF current application. The number of MES depends on the total procedure time and the reached ACT during ablation. The use of contact force monitoring might reduce MES during RF ablation

Influence of caveolin-1 and endothelial nitric oxide synthase on adventitial inflammation in aortic transplants

Background: Restenosis after endovascular interventions is a clinically relevant process that is directly associated with increased morbidity. Thereby, an increased migration and proliferation of vascular smooth muscle cells (VSMCs) is mainly responsible for recurrent lumen narrowing. Previously, we showed that caveolin‑1 (Cav‑1) and endothelial nitric oxide synthase (eNOS) were directly involved in neointimal proliferation. Aims: In the current study, we investigated the impact of Cav‑1 and eNOS on adventitial processes in a murine model. Methods: Denuded aortas from C57Bl6n (wild‑type [WT]), Cav‑1-/, eNOS-/, and Cav‑1-//eNOS-/ mice were transplanted into common carotid arteries of WT mice. The explantation was performed after 6 weeks, followed by Elastica van Gieson staining and immunohistochemistry. Results: The Cav‑1-/ and the eNOS-/ aortas showed an increase in the adventitial content of macrophages, whereas their combined knockout did not lead to additive effects. Differences were observed despite the same acceptor, suggesting the local origin of inflammatory cells. Furthermore, the WT transplants exhibited the highest content of vascular endothelial growth factor A (VEGF‑A) despite the lowest macrophage content. In contrast, the knockout aortas showed a decreased content of VEGF‑A as well as decreased expression of α-smooth muscle actin (α­‑SMA) in the tunica media, suggesting induced VSMC migration. Moreover, the WT aortas exhibited increased neovessel formation. Conclusions: Cav‑1 and eNOS inhibit adventitial macrophage‑derived inflammation and modulate its cellular function. The knockout of Cav‑1 and eNOS leads to a decreased expression of VEGF-A, with decreased neovessel formation and increased migration of VSMCs, which promote a proatherogenic phenotype.

The short term influence of right ventricular pacing burden on echocardiographic and spiroergometric parameters in patients with preserved left ventricular ejection fraction

Background The incidence of worsened clinical outcome due to high right ventricular (RV) pacing burden in patients with preserved left ventricular function remains controversial. Objective To investigate the impact of RV pacing on several echocardiographic and spiroergometric parameters. Methods In 60 pacemaker patients with preserved left ventricular ejection fraction (LVEF) serial echocardiographies and spiroergometries were performed over a time course of 12 months. Additionally, in 48 patients retrospective echocardiographic analyses of the LV- and RV function were carried out up to 24 months after pacemaker implantation. Results The patients were divided into two groups: The high RV pacing burden group (hRVP: ≥ 40%) and the low RV pacing group (lRVP < 40%) according to the definitions in previous randomized MOST and DAVID trials. After a period of 12-month pacemaker therapy no changes to left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), LVEF, E/A-ratio; E/E′-ratio and tricuspid annular plane systolic excursion (TAPSE) could be revealed, independently of the RV pacing burden. Additionally, after 24-month long term follow-up there were no differences in LVEF and TAPSE in both groups. Accordingly, no relevant changes of peak exercise capacity, ventilatory anaerobic threshold or maximal oxygen consumption could be demonstrated independently of the RV pacing. Conclusions In pacemaker patients with preserved LVEF the burden of RV pacing has no adverse influence on several echocardiographic and spiroergometric surrogate parameters of pacemaker-induced cardiomyopathy after a follow-up of 12 to 24 month. Despite this, screening for pacemaker induced cardiomyopathy should be performed especially in the presence of new heart failure symptoms

Long term survival after early unloading with Impella CP

BACKGROUND: The use of percutaneous left ventricular assist devices in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) is evolving. The aim of the study was to assess the long-term outcome of patients with AMICS depending on early initiation of Impella CP((R)) support prior to a percutaneous coronary intervention (PCI). METHODS: We retrospectively reviewed all patients who underwent PCI and Impella CP((R)) support between 2014 and 2016 for AMICS at our institution. We compared survival to discharge between those with support initiation before (pre-PCI) and after (post-PCI) PCI. RESULTS: A total of 73 consecutive patients (69+/-12 years old, 27.4% female) were supported with Impella CP((R)) and underwent PCI for AMICS (34 pre-PCI vs. 39 post-PCI). All patients were admitted with cardiogenic shock, and 58.9% sustained cardiac arrest. Survival at discharge was 35.6%. Compared with the post-PCI group, patients in the pre-PCI group had more lesions treated (p=0.03), a higher device weaning rate (p=0.005) and higher survival to discharge as well as to 30 and 90 days after device implantation, respectively (50.0% vs. 23.1%, 48.5% vs. 23.1%, 46.9 vs. 20.5%, p \u3c 0.05). Kaplan-Meier analysis showed a higher survival at one year (31.3% vs. 17.6%, log-rank p-value=0.03) in the pre-PCI group. Impella support initiation before PCI was an independent predictor of survival up to 180 days after device implantation. CONCLUSIONS: In this small, single-centre, non-randomized study Impella CP((R)) initiation prior to PCI was associated with higher survival rates at discharge and up to one year in AMICS patients presenting with high risk for in-hospital mortality

Comparison of diverse platelet activation markers as indicators for left atrial thrombus in atrial fibrillation

Atrial fibrillation (AF) is well known for being a major risk factor of thromboembolic stroke. We could recently demonstrate an association of monocyte–platelet aggregates (MPAs) with the degree of thrombogenicity in patients with AF. This study investigated platelet activation markers, as potential biomarkers for the presence of left atrial (LA) thrombus in patients with AF. One hundred and eight patients with symptomatic AF underwent transesophageal echocardiography (TEE) before scheduled cardioversion or pulmonary vein isolation. In order to determine the content of MPAs by flow-cytometric quantification analyses, blood was drawn on the day of TEE. The soluble CD40 Ligand (sCD40L) and soluble P-selectin (sP-selectin) were obtained by Cytometric Bead Arrays (CBA). D-dimer levels were detected by quantitative immunological determination of fibrin degradation products. Clinical, laboratory, and echocardiographic standard parameters were obtained from all patients, including the determination of the flow in the left atrial appendage (LAA). Patients with detected LA thrombus (n = 28) compared with patients without thrombus (n = 80) showed an increased number of common risk factors, such as age, diabetes, heart failure, and coronary artery disease (CAD). The presence of LA thrombus was associated with significantly increased levels of MPAs (147 ± 12 vs. 304 ± 29 per µl; p < 0.00), sCD40L (106.3 ± 31.0 vs. 33.5 ± 2.1 pg/ml, p = 0.027), and D-dimer (0.13 ± 0.02 vs. 0.69 ± 0.21 mg FEU/l, p = 0.015). In contrast, sP-selectin showed no association with LA thrombus. A multivariate regression analysis showed that MPAs, sCD40L as well as D-dimers were independent indicators for the existence of LA thrombus. MPAs above 170 cells/µl indicated LA thrombus with a high sensitivity of 93% and a specificity of 73% (OR 62, 95% CI. 6.9–557.2, p < 0.001) in patients with AF, whereas the D-dimer lost their quality as independent indicator by using the conventional cut-off of 0.5 mg/l within the regression analysis. MPAs, as well as the D-dimer, correlated significantly negatively with the flow in the LAA measured during TEE. The content of MPAs, sCD40L, and D-dimer, but not sP-selectin showed an increased dependence on LA thrombus in patients with AF. In our study group, MPAs showed the best diagnostic test accuracy of the compared platelet markers. The different results of the examined platelet activation markers could be an indication of diverse mechanisms of LA thrombus in AF. Further studies should evaluate whether determination of MPAs in clinical routine may suffice to indicate the presence of LA thrombus in patients with AF

Long term survival after early unloading with Impella CP

BACKGROUND:: The use of percutaneous left ventricular assist devices in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) is evolving. The aim of the study was to assess the long-term outcome of patients with AMICS depending on early initiation of Impella CP METHODS:: We retrospectively reviewed all patients who underwent PCI and Impella CP RESULTS:: A total of 73 consecutive patients (69±12 years old, 27.4% female) were supported with Impella CP CONCLUSIONS:: In this small, single-centre, non-randomized study Impella C

Tetrahydrobiopteryna, kofaktor śródbłonkowej syntazy tlenku azotu, chroni odległe obszary miokardium przed apoptozą po wywołanym doświadczalnie zawale serca w warunkach in vivo

Background: Following myocardial infarction (MI), apoptosis occurs early in the remote myocardium and contributes to the processes of myocardial remodelling. Increased nitrosative stress is a well-known and potent inductor of myocardial apopto¬sis. Excess activation of endothelial nitric oxide synthase (eNOS) increases its uncoupling potential and results in nitrosative stress via formation of peroxynitrite. However, the pathophysiological role of eNOS signalling in the remote myocardium after MI is as yet undefined. Aim: The impact of eNOS activation on pro- and anti-apoptotic signalling in the remote myocardium and the influence of pretreatment with the eNOS cofactor tetrahydrobiopterin (BH4) on eNOS activation, nitrosative stress level, and apoptosis induction and execution were studied in a rat MI model in vivo. Results: Twenty-four hours after anterior MI, eNOS activity in animals treated with left anterior descending coronary artery ligation (LIG) significantly increased in the posterior left ventricular (LV) myocardium as did protein nitrosylation when com¬pared to sham treatment. This was paralleled by induction of apoptosis via the extrinsic and intrinsic pathways. Moreover, anti-apoptotic signalling via protein kinase B/Akt and glycogen synthase-kinase 3 beta was suppressed. Notably, pretreatment with the eNOS cofactor BH4 reduced eNOS activation, prevented excess protein nitrosylation, blunted apoptosis induction, facilitated anti-apoptotic signalling, and eventually prevented apoptosis execution. Conclusions: Here we showed that 24 h after experimental MI in rats in vivo, apoptosis was induced in the posterior non-in¬farcted LV wall. Evidence is presented that pretreatment with the eNOS cofactor BH4 resulted in less nitrosative stress and weakened apoptotic processes, although the stabilisers contained did participate in this phenomenon. Because apoptosis is a crucial component of myocardial remodelling, influencing eNOS signalling might be an interesting pharmacological target for the development of novel anti-remodelling therapies.Wstęp: Apoptoza w odległych rejonach miokardium występuje wcześnie po zawale serca (MI) i przyczynia się do remodelingu mięśnia sercowego. Zwiększenie stresu nitrozacyjnego jest znanym silnym czynnikiem wywołującym apoptozę miokardium. Nadmierna aktywacja śródbłonkowej syntazy tlenku azotu (eNOS) zwiększa jej rozprzęganie i powoduje stres nitrozacyjny w wyniku syntezy peroksynitrytu. Jednak nie poznano dotychczas patofizjologicznej roli eNOS w przesyłaniu sygnałów do odległych rejonów miokardium po MI. Cel: Celem niniejszej pracy było przeanalizowanie wpływu aktywacji eNOS na przekazywanie sygnałów pro- i anty-apop¬tycznych w odległych rejonach miokardium oraz wpływu wstępnego leczenia kofaktorem, tetrahydrobiopteryną (BH4) na aktywację NOS, poziom stresu nitrozacyjnego oraz indukowanie i przebieg apoptozy w szczurzym modelu in vivo zawału serca. Wyniki: Dwadzieścia cztery godziny po zawale ściany przedniej stwierdzono istotne zwiększenie w porównaniu z wartościami obserwowanymi w grupie kontrolnej w zakresie aktywności eNOS w miokardium tylnej ściany lewej komory u zwierząt, u których podwiązano gałąź międzykomorową przednią lewej tętnicy wieńcowej, podobnie jak w przypadku nitrozylacji białek. Jednocześnie zaobserwowano indukcję apoptozy zarówno w mechanizmie zewnątrz-, jak i wewnątrzpochodnym. Ponadto zahamowane zostało przekazywanie sygnałów anty-apoptotycznych za pośrednictwem ścieżki sygnałowej kinazy proteinowej B/Akt i kinazy syntazy glikogenu 3 beta. Warto zaznaczyć, że podanie wcześniej kofaktora eNOS, BH4, zmniejszyło aktywację eNOS, zapobiegło nadmiernej nitrozylacji białek, stłumiło indukcję apoptozy, ułatwiło przekazywanie sygnałów anty-apoptotycznych i zatrzymało proces apoptozy. Wnioski: Wykazano, że 24 godziny po wywołanym eksperymentalnie MI u szczurów in vivo nastąpiła indukcja apoptozy w tylnej ścianie lewej komory nieobjętej zawałem. Przedstawiono dowody naukowe potwierdzające, że wcześniejsze podanie kofaktora eNOS, BH4, spowodowało zmniejszenie stresu nitrozacyjnego i osłabienie procesów apoptozy, chociaż zawarte w nim stabilizatory miały w tym swój udział. Ze względu na to, że apoptoza jest ważnym elementem remodelingu miokar¬dium, oddziaływanie na ścieżkę sygnałową eNOS może być interesującym celem leczenia w opracowywaniu nowych terapii przeciwdziałających remodelingowi

Association of platelet activation markers with recurrence of atrial fibrillation after pulmonary vein isolation

Atrial fibrillation (AF) is known to cause platelet activation. AF and its degree of thrombogenesis could be associated with monocyte-platelet aggregates (MPAs). We investigated on whether the content of MPAs or other platelet activation markers is associated with the recurrence of AF after pulmonary vein isolation (PVI). A total of 73 patients with symptomatic AF underwent PVI. After 6 months, all patients were evaluated for episodes of AF recurrence. At the same time, flow-cytometric quantification analyses were performed to determine the content of MPAs. Further platelet activation parameters were detected by using either cytometric bead arrays or quantitative immunological determination. Patients with recurrent AF (n = 20) compared to individuals without AF relapse (n = 53) were associated with an increased content of MPAs (43 ± 3% vs. 33 ± 2%, p = 0.004), as well as an increased CD41 expression on monocytes (191 ± 20 vs. 113 ± 6, p = 0.001). The level of the soluble platelet activation markers such as D-dimer, sCD40L, and sP-selectin did not differ between these groups. The content of MPAs correlated weakly with the level of sCD40L (r = 0.26, p = 0.03), but not with sP-selectin and D-dimer, whereas sP-selectin and sCD40L correlated with each other (r = 0.38, p = 0.001). Only the cellular marker of platelet activation, the content of MPAs, was increased in patients with recurrent AF after PVI. In contrast, soluble markers remained unaltered. These data indicate a distinct mechanism and level of platelet activation in AF. The clinical relevance of MPAs in identifying AF recurrence or in guiding the therapy with anticoagulants remains to be elucidated