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Background: Left ventricular global longitudinal strain (LV GLS) is a superior predictor of adverse cardiac events in patients with myocardial infarction and heart failure. We investigated the ability of morphological features of infarcted myocardium to detect acute left ventricular (LV) dysfunction and predict LV functional recovery after three months in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods: Sixty-six STEMI patients were included in the C-reactive protein (CRP) apheresis in Acute Myocardial Infarction Study (CAMI-1). LV ejection fraction (LVEF), LV GLS, LV global circumferential strain (LV GCS), infarct size (IS), area-at-risk (AAR), and myocardial salvage index (MSI) were assessed by CMR 5 ± 3 days (baseline) and 12 ± 2 weeks after (follow-up) the diagnosis of first acute STEMI. Results: Significant changes in myocardial injury parameters were identified after 12 weeks of STEMI diagnosis. IS decreased from 23.59 ± 11.69% at baseline to 18.29 ± 8.32% at follow-up (p < 0.001). AAR and MVO also significantly reduced after 12 weeks. At baseline, there were reasonably moderate correlations between IS and LVEF (r = −0.479, p < 0.001), LV GLS (r = 0.441, p < 0.001) and LV GCS (r = 0.396, p = 0.001) as well as between AAR and LVEF (r = −0.430, p = 0.003), LV GLS (r = 0.501, p < 0.001) and weak with LV GCS (r = 0.342, p = 0.020). At follow-up, only MSI and change in LV GCS over time showed a weak but significant correlation (r = −0.347, p = 0.021). Patients with larger AAR at baseline improved more in LVEF (p = 0.019) and LV GLS (p = 0.020) but not in LV GCS. Conclusion: The CMR tissue characteristics of myocardial injury correlate with the magnitude of LV dysfunction during the acute stage of STEMI. AAR predicts improvement in LVEF and LV GLS, while MSI is a sensitive marker of LV GCS recovery at three months follow-up after STEMI.

Objective: Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency.Approach and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling.Conclusions: Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.

Background Severe heart rhythm disturbances (SHRDs) occur regularly in cardiogenic shock (CS). Percutaneous left ventricular assist devices (pLVADs) can actively unload the left ventricle (LV), decreasing left ventricular end-diastolic pressure and wall tension, which are suspected parameters for the induction and maintenance of arrhythmias. The aim of this study was to describe effects of LV unloading on SHRD. Method In the Dresden Impella Registry, 97 patients received an Impella CP in refractory CS. Of them, 19 had SHRDs, which were not stopped by common therapeutic strategies such as electrical defibrillation or antiarrhythmic drugs. They were only stopped after implantation of a micro-axial heart pump. This phenomenon was referred to as heart rhythm stabilisation (HRS). Clinical outcome and laboratory parameters were assessed and risk factors for the occurrence of HRS were identified. Results All 19 patients with refractory SHRD terminated immediately into a stable heart rhythm after insertion of the micro-axial heart pump. In 37% no additional defibrillation was needed. Of the patients with HRS, CS was mostly caused by myocardial infarction (68%). Resuscitation before pLVAD was performed in 89% for more than 30 minutes. Patients with HRS were resuscitated more frequently and for a longer duration than patients without HRS. After HRS, the serum lactate and norepinephrine dosage decreased in the first 12 hours, whereas left ventricular ejection fraction increased by 95%. Conclusions Left ventricular unloading in patients with CS seems to be an option for treating patients with sustained life-threatening tachycardia, who are refractory to common treatment.

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 key players of the hypoxic response are the hypoxia-inducible factors (Hif), whose α-subunits are tightly regulated by Prolyl-4-hydroxylases (PHD), predominantly by PHD2. Monocytes/Macrophages are involved in atherosclerosis but also restenosis and were found at hypoxic and sites of the lesion. Little is known about the role of the myeloid PHD2 in atherosclerosis and neointima formation. The study aimed to investigate the consequences of a myeloid deficiency of PHD2 in the process of neointima formation using an arterial denudation model. LysM-cre mice were crossed with PHD2

An excessive inflammatory reaction after acute myocardial infarction (AMI) is known to be harmful. New anti-inflammatory therapies are required. This study assessed the predictive role of early CRP in patients with STEMI. A total of 1003 patients with STEMI were analysed. A total of 180 patients with proven infection were excluded. CRP after 12, 24 and 48 h after pain onset were evaluated. Of 823 patients, 103 (12.5%) died within one year after AMI. The deceased patients showed higher CRP, even after already 12 h (6 vs. 13 mg/l, p vs. 25 mg/l, p vs. 92 mg/l, p p = .03), after 24 h: CRP ≥ 18 mg/l in 44% (OR: 2.5, p = .03), after 48 h: CRP ≥ 53 mg/l in 44% (OR 1.9, p = .03). Early CRP values correlated strongly with the later maximum value of CRP (p Already early CRP values are accurate for risk-prediction following AMI. By identifying patients who are beginning to develop an excessive inflammatory response, it may be possible to identify those who benefit from anti-inflammatory therapies.

Background The CAMI-1 study dealt with the depletion of CRP by apheresis in patients with acute myocardial infarction (AMI). CRP, the prototype human acute phase protein, has been known as a marker of poor prognosis in AMI and independently predicts 30-day mortality. Methods 66 STEMI patients were enrolled following complete coronary revascularization (2–12 h after AMI). 32 patients received CRP apheresis, whereas 34 patients treated by standard protocols served as controls. CRP apheresis started 24±12 h and 48±12 h after onset of symptoms. A specific CRP adsorber removed ≤79% of the original CRP. 6000 ml of plasma was treated via peripheral venous access. Primary endpoint was myocardial infarction size as determined by Cardiac Magnetic Resonance Imaging (CMR) 3–9 days after STEMI. Results Aphereses sessions were well tolerated with no relevant side effects. The expected peak CRP level after AMI can be calculated precisely with 2–3 CRP quantifications during the first 24h after the onset of symptoms (CRP gradient). The regression coefficient for this analysis is 0.91. This mathematical step allows for the comparison of the CRP-apheresis group and the controls on the basis of their individual CRP gradients. The mean CRP gradient does not differ between both groups, whereas the mean area under the curve (AUC) of CRP within the first 72 h after AMI does. Thus, there was no bias in CRP kinetics between the two groups. The AUC of CRP is a significant indicator for infarct size (p=0.002), LVEF (p Conclusions For the first time we find an unequivocal association between myocardial infarct size and the AUC of CRP. The results show a significant beneficial effect of CRP apheresis on myocardial infarction size and wall motion. Selective CRP apheresis is now being further evaluated as a therapeutic approach in the treatment of acute myocardial infarction in a registry (CAMI registry). Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Pentracor GmbH

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 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.

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.

Aim of the study Frail patients with high grade aortic valve stenosis (AS) undergoing Transcatheter Aortic Valve Implantation (TAVI) have an increased mortality. A connection between frailty and inflammation has been suggested. Monocyte subpopulations are associated with both cardiovascular diseases and chronic inflammatory diseases. This study investigates the association of frailty with monocyte subpopulations and systemic inflammatory parameters in elderly patients undergoing TAVI. Methods A total of 120 patients with symptomatic AS was examined. Before TAVI implantation, frailty was assessed by a bedside evaluation (eyeball test). In all patients a flow cytometry analysis has been performed. Monocyte subpopulations were defined as follows: classical (CD14++CD16−), intermediate (CD14++CD16+) and non-classical (CD14+CD16++). Expression of CD11b was measured as a marker for monocyte activation. Pro-inflammatory cytokines such as interleukin IL-8, as well as CRP were measured with Cytometric Bead Array or standard laboratory methods. Results 28 out of 120 patients were frail. These patients showed both, signs of elevated chronic systemic inflammation reflected by elevated CRP (3.7 (1.4–5.4) vs. 5.9 (3.7–29.1), p = 0.001) and an elevated level of intermediate monocytes (37 (24–54) vs. 53 (47–63), p = 0.001). At 6 months after TAVI, 19 of 120 patients died, primarily without relevant dysfunction of the implanted aortic valve. Mortality was significantly higher in the frail as compared with non-frail patients (9 of 28 frail patients vs. 10 of 92 non frail patients, p Conclusion Chronic systemic inflammation and increased levels of intermediate monocytes are associated with frailty in old patients with severe aortic valve stenosis. Both the syndrome of frailty and elevated intermediate monocytes showed an association with early mortality after TAVI.

Background The CAMI-1 study dealt with the depletion of CRP by apheresis in patients with acute myocardial infarction (AMI). CRP, the prototype human acute phase protein, has been known as a marker of poor prognosis in AMI and independently predicts 30-day mortality. Methods 66 STEMI patients were enrolled in the study following complete coronary revascularization (2–12 h after the onset of symptoms). 32 patients received CRP apheresis, whereas 34 patients treated by standard protocols served as controls. CRP apheresis started 24±12 h and 48±12 h after onset of symptoms. In case of a rapid increase in CRP plasma levels following the 2nd session, a 3rd session was carried out another 24 h later. A specific CRP adsorber removed up to 79% of the original CRP. In each apheresis session, 6000 ml of plasma was treated via peripheral venous access. Primary study endpoint was myocardial infarction size as determined by Cardiac Magnetic Resonance Imaging (CMR) 2–9 days after STEMI. Results Aphereses sessions were well tolerated with no relevant side effects. Peak CRP plasma levels after STEMI ranged from 9 to 279 mg/l. The expected peak CRP level after AMI can be calculated precisely with 2–3 CRP quantifications during the first 24 h after the onset of symptoms. The regression coefficient for this analysis is 0.91. This mathematical step allows for the comparison of the CRP-apheresis group and the controls on the basis of their individual CRP peak levels. The statistical evaluation shows that the CRP concentration is significantly associated with the damage (infarct size, LVEF, circumferential strain) in the controls. This association was lost in the aphereses patients: they performed significantly better at all endpoints (infarct size, LVEF, circumferential strain) than the controls. The CRP apheresis significantly reduced myocardial damage. To our surprise, two apheresis patients had an infarct size of 0%. Conclusions For the first time we find an unequivocal association between myocardial infarct size and the CRP concentration. This is in some respects a surprise, since the basic assumption in AMI is that the vascular occlusion leads to primary damage and the reperfusion to secondary damage, which would not have led one to expect such a clear dose-response relationship as that observed here. In addition, our results show a significant beneficial effect of CRP apheresis on myocardial infarction size and wall motion. Selective CRP apheresis is now being further evaluated as a therapeutic approach in the treatment of acute myocardial infarction in a registry (CAMI registry). Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Pentracor GmbH

Introduction Patients with frailty represent an increasing patient group in the intensive care medicine. A connection between frailty and inflammation has been suggested. An increased mortality rate in patients with high grade aortic valve stenosis (AS) and frailty, who underwent Transcatheter Aortic Valve Implantation (TAVI) has been observed. A systemic inflammatory reaction in the intensive care unit in the first days after TAVI is a positive predictive factor for an unfavorable outcome. Exact mechanisms are still not fully explained. Monocyte subpopulations are associated with both cardiovascular diseases and a high APACHE II score in critically ill patients. Purpose This study investigates the correlation between frailty and cellular and systemic inflammatory mechanisms and mortality after TAVI. Methods We examined 120 patients with symptomatic AS who underwent TAVI. Before the implantation, frailty status has been assessed. In all patients a flow cytometry analysis has been performed. Monocyte subpopulations were defined as follows: Mon1 (CD14++CD16–), Mon2 (CD14++CD16+) and Mon3 (CD14+CD16++). Expression of CD11b has been measured as a marker for monocyte activation. Pro-inflammatory cytokines such as interleukin IL-8, as well as CRP have been measured with Cytometric Bead Array or standard laboratory methods. Results After 3 months 15 of 120 patients died, primarily without relevant dysfunction of the implanted aortic valve. In 8 of 15 (53%) of the deceased patients and 20 of 100 (19%) of the surviving patients, frailty could be diagnozed before TAVI (p=0.003). Patients with frailty showed prior to TAVI signs of chronic inflammation: elevated CRP (3.7 vs. 5.9 mg/l, p=0.001) and elevated levels of considered as pro-inflammatory Mon2 monocytes (37 vs. 53, p=0.001). Expression of CD11b and IL-8 showed an increasing trend in patients with frailty. Frailty, the monocyte markers, IL-8 and CRP prior to TAVI correlated with increased early mortality after TAVI. Conclusion A considerable number of elderly patients with high grade aortic valve stenosis can be described as frail. This syndrome is associated with increased mortality and with signs of chronic systemic inflammation and pro-inflammatory monocytes. Funding Acknowledgement Type of funding source: Private hospital(s). Main funding source(s): Heart Center Dresden

Background: C-reactive protein (CRP) is a well-known marker of inflammation. It is less known that CRP mediates tissue damage in acute myocardial infarction (AMI) thus potentially worsening prognosis. A newly developed specific CRP adsorber allows efficient lowering of CRP levels and may improve survival.Objectives: Aim of this multi-center, controlled, non-randomized first-in-man CRP apheresis in Acute Myocardial Infarction study (CAMI-1) was to investigate the relationship between CRP levels (CRP gradient), myocardial infarct size and function as well as safety and efficacy of CRP apheresis in the setting of acute ST-segment Elevation Myocardial Infarction (STEMI) in humans.Methods: Eighty-three patients (45 apheresis, 38 controls) were recruited. CRP apheresis was performed 24 ± 12, 48 ± 12, and optionally 72 ± 12 h after onset of symptoms. First aphereses were performed at a median CRP concentration of 23.0 mg/L (range 9–279). In each apheresis session, 5,900 ± 400 mL plasma was processed via peripheral venous access. Primary study endpoint was a reduction in myocardial infarct size after STEMI as determined by cardiovascular magnetic resonance (CMR).Results: In controls, the CRP concentration significantly correlated with infarct size (p = 0.002) and decreased myocardial function (p ≤ 0.001). The CRP concentration in apheresis patients did not correlate with infarct size (p = 0.66) or left ventricular (LV) function (p = 0.79) and global strains and therefore significantly differed from controls (p = 0.03 and p = 0.002). Three major adverse cardiac events occurred in the control group after 12 months, none occurred in the apheresis group. Mean CRP depletion achieved over all apheresis procedures was 53.0 ± 15.1%. Apheresis sessions were well-tolerated. Reduced infarct size in the apheresis group compared to the control group (primary endpoint) was not achieved according to the original statistical analysis plan. Taking into account the individual CRP levels, however, revealed significant results. Modifications of the analysis plan were introduced in order to recruit a sufficient number of patients.Conclusions: This pilot study in humans reveals a correlation between CRP concentration and myocardial infarct size. CRP concentrations in STEMI can effectively be reduced by CRP apheresis without relevant side effects. CRP apheresis has the potential to interfere with deleterious aspects of STEMI. By lowering CRP levels, it resulted in the loss of correlation of CRP concentrations with myocardial infarct sizes as well as LV function. These results encourage a larger, randomized clinical trial.Clinical Trial Registration:https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008988, DRKS00008988.

Background In the first three months after Transcatheter aortic valve implantation (TAVI), a remarkable number of patients have an unfavorable outcome. An inflammatory response after TAVI is suspected to have negative effects. The exact mechanisms remain unclear. We examined the influence of monocyte subpopulations on the clinical outcome, along with the degree of monocyte activation and further parameters of inflammation and platelet activation. Methods Flow-cytometric quantification analyses of peripheral blood were done in 120 consecutive patients who underwent TAVI (one day before TAVI and on day 1 and 7 after TAVI). Monocyte-subsets were defined by their CD14 and CD16 expression, monocyte-platelet-aggregates (MPA) by CD14/CD41 co-expression. The extent of monocyte activation was determined by quantification of CD11b-expression (activation epitope). Additionally, pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, C-reactive protein were measured with the cytometric bead array method or standard laboratory tests. Results Elevated Mon2 (CD14++CD16+) - monocytes (38 vs. 62 cells/μl, p Conclusions Elevated Mon2-monocytes and a high level of monocyte activation before TAVI are associated with early mortality after TAVI. Chronic inflammation in aging patients seems to be an important risk factor after 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 &lt, 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.

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® support prior to a percutaneous coronary intervention (PCI). Methods: We retrospectively reviewed all patients who underwent PCI and Impella CP® 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® 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 < 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® 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.

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.

Chromogranin B (CGB) regulates B-type natriuretic peptide (BNP) production. Circulating CGB levels are elevated in heart failure (HF) animal models and HF patients, but also increase in healthy individuals in response to physical activity. Therefore, CGB seems to integrate information from myocardial stress and systemic neuro-endocrine activation. Substantial gaps remain in our understanding of CGB regulation in HF.We conducted a retrospective registry study including 372 patients. CGB and N-terminal pro-BNP (NT-proBNP) plasma levels were assessed in acute HF and chronic valvular HF patients and controls. CGB levels were significantly increased in acute HF and chronic valvular HF, but significantly higher in the latter. Patients in chronic valvular HF with severe mitral regurgitation (cHF-MR) showed significantly higher CGB levels than patients in chronic valvular HF with severe aortic stenosis. CGB levels progressively increased with worsening NYHA functional status and were moderately correlated to NT-proBNP, but independent of left ventricular (LV) ejection fraction (LVEF), LV mass, age and body weight. Finally, cHF-MR patients showed significant reductions of CGB levels after interventional mitral valve repair.CGB is a promising emerging biomarker in HF patients with unique potential to integrate information from myocardial stress and neuro-endocrine activation.

BACKGROUND Interventional mitral valve (MV) repair of severe symptomatic mitral regurgitation (MR) is a therapeutic option in high-risk surgical or inoperable patients. Assessment of the MV remains a crucial part of pre-interventional screening. Three-dimensional transoesophageal echocardiography (3D-TOE) may compensate for well-known pitfalls that occur in 2D-TOE. PURPOSE We investigated whether the functional length of the central segments of the posterior and anterior MV leaflets (PML-P2 and AML-A2) is more reliably determined by 3D-TOE full volume datasets (3D-MPR) or orthogonal biplane-imaging (Xplane) when compared to 2D-TOE. METHODS AND RESULTS Between February 2014 and August 2015, 265 consecutive patients with moderate to severe symptomatic MR were screened. Seventy patients were judged suitable for interventional MV repair by the in-house Heart-Team. Eventually, 59 patients remained for data analysis. Inter-observer variability was lowest in 3D-MPR followed by Xplane (r = 0.92 and 0.90, p

Platelet transfusion is an effective option to reverse platelet inhibition in thienopyridine-treated patients suffering from bleedings or requiring urgent surgery. However, in ticagrelor-treated patients, the previous studies revealed significant clinical effects to platelet rich plasma (PRP) but poor response to pooled platelets (PP) as used in clinical routine. The aim of this study was to elucidate a potential pathomechanism to explain the poor response of ticagrelor to PP. From 79 whole blood samples of patients treated with ticagrelor, prasugrel, or clopidogrel, the PRI-VASP was determined before and after in vitro platelet supplementation of PP or PRP at increasing concentrations. Compared to prasugrel- and clopidogrel-treated patients, the PRI-VASP of ticagrelor-treated patients showed no significant increase after in vitro administration of PP. PRI-VASP was performed in ticagrelor-treated samples after in vitro addition of 1: centrifuged PRP platelets resuspended in PP buffer, 2: PP with human serum, 3: human serum alone. Surprisingly, PP with human serum or human serum alone were able to significantly increase PRI-VASP in samples of ticagrelor-treated patients (11.7 ± 10.9 → 61.3 ± 10.9%, p = 0.006; 11.7 ± 10.9 → 54.1 ± 2.7%, p

Kontext: Starsi studie prokazaly, že se objem, hmota a funkce leve (LK) a prave komory (PK) srdecni významně lisi podle toho, zda se při výpoctu těchto parametrů zahrnou svalove tramce a papilarni svaly (trabeculae papillary and papillary muscle, TPM).Metody: V kohortě 101 pacientů bylo provedeno vysetřeni srdce magnetickou rezonanci (cardiac magnetic resonance, CMR). Kohorta zahrnovala celkem 26 pacientů bez patologických nalezů na CMR (referencni skupina), pacienty s ischemickou kardiomyopatii (IKMP), s dilatacni kardiomyopatii (DKMP) a pacienty s hypertrofii leve komory (vždy po 25 pacientech). Parametry LK a PK se stanovovaly pomoci dřive zavedených metod: 1. metoda zahrnujici TPM a 2. metoda nezahrnujici TPM do objemu přislusneho srdecniho oddilu.Výsledky: Ve srovnani s výpoctem při zahrnuti TPM znamenalo vylouceni TPM z celkoveho objemu LK a PK významně mensi objem na konci diastoly a systoly (end-diastolic and end-systolic volume, EDV, ESV) a hmotu myokardu, a vyssi hodnoty tepoveho objemu (stroke volume, SV) a ejekcni frakce (EF) (p = 0.001). Podil TPM na hmotě LK a PK byl větsi u DKMP (18,4 ± 3,8 %) a IKMP (17,8 ± 3,2 %) než u referencni skupiny (15,2 ± 2,5 %; oboji p < 0,05); výsledkem byl statisticky významně větsi rozdil mezi oběma použitým metodami (1. metoda - 2. metoda) při výpoctu ESV, EDV, SV, EF a hmoty myokardu u nemocných s DKMP a IKMP oproti referencni skupině.Zavěr: Hodnoty parametrů LK při vysetřeni srdce MR významně ovlivňuje to, zda jsou TPM považovany za soucast krevniho poolu LK nebo za soucast hmoty LK. Aby se zabranilo chybne interpretaci výsledků vysetřeni a chybným rozhodnutim, může být při dlouhodobem sledovani pacientů naprosto zasadni systematicke použivani jedne z obou metod delineace LK.

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; p0.00), 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, p0.001) 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.

Aims It is hypothesized that inflammation could promote structural and electrical remodelling processes in atrial fibrillation (AF). Atrial infiltration of monocytes and granulocytes has been shown to be dependent on CD11b expression. The aim of this study was to investigate whether treatment of AF by pulmonary vein isolation (PVI) may lead to reduced inflammation, as indicated by a decrease of CD11b expression on monocytes and granulocytes. Methods and results Flow-cytometric quantification analysis and determination of systemic inflammatory markers of peripheral blood were performed in 75 patients undergoing PVI 1 day before and 6 months after PVI. The extent of activation of monocytes and granulocytes was measured by quantifying the cell adhesion molecule CD11b. The mean expression of CD11b on monocytes (20.9 ± 2.5 vs. 10.2 ± 1.4; P

Background Inflammation is increasingly recognized as an important pathogenic feature in cardiovascular disease. In patients with STEMI, C-reactive protein (CRP), the prototype human acute phase protein, is a marker of poor prognosis and independently predicts 30-day mortality. In STEMI, CRP may indeed be intimately involved in myocardial damage by activating the complement system in the ischemic tissue. In animal experiments, CRP removal after STEMI reduces infarct size and results in a significantly better left ventricular ejection fraction (LVEF). Recently, in the multi-center matched-control pilot study on CRP apheresis in Acute Myocardial Infarction (CAMI1), a newly designed CRP adsorber has been demonstrated to efficiently and selectively lower CRP plasma levels in humans. Here, we present preliminary data of the ongoing trial. Methods Up to the present day, 67 STEMI patients were enrolled in the study following complete coronary revascularization. 32 patients received CRP apheresis, whereas 35 patients treated by standard protocols served as controls. CRP apheresis started 24±12 h and 48±12 h after onset of symptoms. In case of a rapid increase in CRP plasma levels following the 2nd session, a 3rd session was carried out another 24 h later. In each apheresis session, 6000 ml plasma was treated via peripheral venous access. Primary study endpoint was myocardial infarction size as determined by Cardiac Magnetic Resonance Imaging (MRI) 5±3 days after STEMI. Results Apheresis sessions were well tolerated with no relevant side effects. Peak CRP plasma levels after STEMI ranged from 12 mg/l to 279 mg/l. The peak CRP level after AMI can be calculated precisely with at 2–3 CRP quantifications during the first 24 h after the onset of symptoms. The regression coefficient for this analysis is 0.95. This mathematical step allows for the comparison of the CRP-apheresis group and the controls on the basis of their individual CRP peak levels. The statistical evaluation shows that the apheresis patients no longer correlate with the control with regard to the endpoints infarct size, LVEF, longitudinal strain and circumferential strain. They perform significantly better at all endpoints. The CRP apheresis reduced the development of myocardial damage. Conclusions Here, an unequivocal association between infarct size and CRP is demonstrated for the first time. CRP apheresis following STEMI is feasible and safe. Our preliminary results in a small cohort show a significant beneficial effect of CRP apheresis on myocardial infarction size and wall motion. Selective CRP apheresis may emerge as a new therapeutic approach in the treatment of acute myocardial infarction.

Background Cardiogenic shock (CS) is often associated with severe heart rhythm disturbances (SHRD). Percutaneous left ventricular assist devices (pLVAD) can actively unload the left ventricle (LV) using a micro-axial pump and resulting in a decreased end-diastolic pressure and wall tension. These parameters are suspected to induce and maintain rhythmological instability. Purpose In the current study, we firstly describe the termination of SHRD immediately (less than 5 minutes) after LV-unloading in CS patients with previous unsuccessful antiarrhythmic treatment. Methods The Dresden Impella Registry is an ongoing single center registry. Since 2014, a total of 97 patients were included. Each of whom had received a micro-axial heart pump in refractory CS supplying a circulatory support of 3.5 l/min. We investigated the subgroup of patients which initially exhibited SHRD like ventricular tachycardia or ventricular fibrillation, and showed an immediately stabilization of heart rhythm directly after insertion of pLVAD (HRS). This subgroup was compared with the other patients of the registry (NHRS). Therefore, clinical laboratory and hemodynamic parameters were measured and analyzed. Results In 19 patients of the registry a HRS was observed. Among these patients, a CPR before pLVAD was performed in 89.5% with a mean duration of 30.7min, whereby 52.6% sustained an in-hospital cardiac arrest and 36.9% an out-of-hospital cardiac arrest respectively. In the NHRS subgroup (n=78), a CPR was performed less frequently (39.7%; p The mortality showed no differences between the HRS and NHRS cohort at 30 days (68.4% vs. 58.1%; p=0.413) and 90 days (78.9% vs. 66.7%; p=0.306), despite a more frequent and longer CPR with a higher ratio of out-of-hospital cardiac arrests among the HRS patients. There was also no difference in mortality between patients, who received an in-hospital CPR. However, HRS patients with in-hospital CPR showed a significantly lower serum lactate and NA dosage compared to the NHRS cohort (Figure A & B). Furthermore, NA recovery, defined as 50% decrease as compared to the initial NA dosage, occurred more frequently in the HRS group (HRS 42.9% vs. NHRS 7.1%; p=0.049). The LVEF nearly double in the HRS subgroup after LV-unloading, whereas it did not change in the NHRS subgroup (relative LVEF increase: HRS 95% vs. NHRS 15%). Figure A & B Conclusion The termination of SHRD due to LV-unloading occurred in around 20% of CS patients in Dresden Impella Registry and was associated with a lower serum lactate and NA dosage as well as an improved LVEF among patients with in-hospital CPR. Acknowledgement/Funding None

Chromogranin B and inositol 1,4,5-trisphosphate-associated calcium signaling leading to increased natriuretic peptide production has been described in cardiac hypertrophy. Here, we performed left anterior descending coronary artery ligation in rats as a model for systolic heart failure and examined protein and gene expression clusters in the infarcted and noninfarcted myocardium and moreover under treatment with metoprolol. We found that atrial natriuretic peptide gene transcription was significantly more elevated in the infarcted compared with the noninfarcted myocardium. Chromogranin B, which facilitates calcium release from internal stores through the inositol 1,4,5-trisphosphate receptor, was upregulated in both areas. Interestingly, angiotensin II receptor type 1 gene transcription was significantly upregulated in the infarcted and unchanged in the noninfarcted myocardium. Nuclear factor ĸappa B as a calcium-dependent transcription factor showed increased activity in the infarction zone. The β-adrenergic axis does not seem to be involved, as metoprolol treatment did not have a significant impact on any of these results. We conclude that region-specific upregulation of angiotensin II receptor type 1 is a major factor for increased atrial natriuretic peptide production in the infarcted anterior wall. This effect is most likely achieved through inositol 1,4,5-trisphosphate-mediated cytosolic calcium increase and subsequent nuclear factor ĸappa B activation, which is a known transcription factor for natriuretic peptides.

Background: This study evaluated the wearable cardioverter-defibrillator (WCD) for use and effectiveness in preventing sudden death caused by ventricular tachyarrhythmia or fibrillation. Methods: From April 2010 through October 2013, 6043 German WCD patients (median age, 57 years; male, 78.5%) were recruited from 404 German centers. Deidentified German patient data were used for a retrospective, nonrandomized analysis. Results: Ninety-four patients (1.6%) were treated by the WCD in response to ventricular tachyarrhythmia/fibrillation. The incidence rate was 8.4 (95% confidence interval, 6.8–10.2) per 100 patient-years. Patients with implantable cardioverter-defibrillator explantation had an incidence rate of 19.3 (95% confidence interval, 12.2–29.0) per 100 patient-years. In contrast, an incidence rate of 8.2 (95% confidence interval, 6.4–10.3) was observed in the remaining cardiac diagnosis groups, including dilated cardiomyopathy, myocarditis, and ischemic and nonischemic cardiomyopathies. Among 120 shocked patients, 112 (93%) survived 24 hours after treatment, whereas asystole was observed in 2 patients (0.03%) with 1 resulting death. ConclusionS: This large cohort represents the first nationwide evaluation of WCD use in patients outside the US healthcare system and confirms the overall value of the WCD in German treatment pathways.

SummaryA growing body of evidence suggests a pivotal role of inflammatory processes in AF in a bidirectional manner. Infiltrating leukocytes seem to promote both structural and electrical remodelling processes in patients with AF. Monocyte-platelets-aggregates (MPAs) are sensitive markers of both platelets and monocyte activation. So far it is not clear whether the content of MPAs is affected by AF. The present study examined the content of MPAs and the activation of monocytes in elderly patients with an aortic stenosis in dependence of AF. These patients are known to have a high prevalence of AF. Flow-cytometric quantification analysis demonstrated that patients with AF have an increased content of MPAs (207 ± 13 cells/μl vs 307 ± 21 cells/μl, pSupplementary Material to this article is available online at www.thrombosis-online.com.

Pacient s cevnim typem Ehlersova-Danlosova syndromu a s implantovanou mechanickou chlopni byl hospitalizovan pro dyspnoe a bolest na hrudi. Po vylouceni infarktu myokardu nasledovalo vysetřeni CT angiografii, ktere prokazalo spontanni rupturu jedne z mezižebernich tepen s nasledným vznikem hemothoraxu a rozvojem kompresivni atelektazy. Celý připad komplikovala soucasna antikoagulacni lecba warfarinem po implantaci mechanicke chlopně. Po neuspěsne konzervativni lecbě byl připad řesen chirurgicky. Jak ukazuje nase kasuistika, může implantace mechanicke chlopně s nezbytnou odpovidajici a dlouhodobou antikoagulaci warfarinem u těchto pacientů představovat nežadouci přidatne riziko.

An inflammatory systemic reaction is common after Transcatheter Aortic Valve Implantation (TAVI). We recently reported about an involvement of Mon2-monocytes, the CD11b expression on monocytes and parameters of systemic inflammation before TAVI correlating with early mortality after TAVI. Here, we provide data of monocyte subpopulations, CD11b expression and parameters of a systemic inflammation in dependence of three-month mortality after TAVI. With this, we provide further insights into inflammatory mechanism after TAVI. The data were collected by flow-cytometric quantification analyses of peripheral blood in 120 consecutive patients who underwent TAVI (on day 1 and 7 after TAVI). Monocyte-subsets were identified by their CD14 and CD16 expression and monocyte-platelet-aggregates (MPA) by CD14/CD41 co-expression. The extent of monocyte activation was determined by quantification of CD11b-expression (activate epitope). Additionally, pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, C-reactive protein, procalcitonin were measured using the cytometric bead array method or standard laboratory tests. Additionally, we report procedural outcomes in dependence of three-month mortality. Furthermore, correlations of CD11b-expression on monocytes with parameters of platelet activation or further inflammatory parameters are presented. For further interpretation of the presented data, please see the research article “Mon2-Monocytes and Increased CD-11b Expression Before Transcatheter Aortic Valve Implantation are Associated with Earlier Death” by Pfluecke et al. [1]

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 CPWe retrospectively reviewed all patients who underwent PCI and Impella CPA total of 73 consecutive patients (69±12 years old, 27.4% female) were supported with Impella CPIn this small, single-centre, non-randomized study Impella CP

A strong interdependence is known between atrial fibrillation (AF), inflammation and thrombogenesis. Monocyte–platelet aggregates (MPAs) are sensitive markers of platelets and monocyte activation. It is not known whether MPAs are associated with thrombogenicity in AF. Therefore, we examined differences in the content of MPAs and CD11b expression in patients with AF in dependence of the presence of atrial thrombus formation. 107 patients with symptomatic AF underwent transesophageal echocardiography (TEE) before planned cardioversion or pulmonary vein isolation. Flow-cytometric quantification analysis was done on the day of performed TEE to determine the content of MPAs and the expression of CD11b on monocytes and granulocytes. Compared to patients without thrombus (n = 80) those with an echocardiographic proven left atrium (LA) thrombus (n = 27) showed an increased extent of the risk factors age, diabetes and heart failure. The content of MPAs (147 ± 12 vs. 311 ± 29 cells/µl, p

Background Monocytes can be differentiated into subpopulations depending on their expression profile of CD14 and CD16. CD16-positive monocytes are associated with coronary artery disease. Up to now, no data exist about the effect of lipoprotein apheresis (LA) on the distribution of monocyte subpopulations. Methods 80 patients who underwent LA at the University Hospital Dresden were included in the study. 8 out of the 80 LA patients received LA for the first time at the time point of blood analysis. Six different methods of LA were used (H.E.L.P. n = 8; Liposorber D n = 10; LF n = 14; DALI n = 17; MONET n = 11; Therasorb ® LDL n = 12). Blood samples were taken immediately before and after LA and analyzed for CD14 and CD16 expression on monocytes. A total of 42 patients with cardiovascular risk factors but no indication for LA served as control group. Results The composition of monocyte-population was analyzed in regard to the 3 subpopulations. After LA, an increase in classical monocytes (CD14 ++ CD16 − ) (93.3% vs. 93.9%, p + CD16 + ) (1.5% vs 1.0%; p ++ CD16 + ) (5.3% vs. 5.1%). Two methods (MONET and Therasorb ® LDL) did not influence the distribution of monocyte subpopulations. Interestingly, patients with LDL-C above 2.5 mmol/l prior LA showed increased amounts of intermediate monocytes. Conclusion The distribution of monocyte populations is influenced by LA but depends on the distinct method of LA. Influences of LA were mainly observed in the content of classical and non-classical monocytes, whereas the intermediate monocyte population remained unaltered by LA.

AIMS We aimed to evaluate possible detrimental effects of transoesophageal echocardiography (TEE) on the oesophageal tissue during percutaneous mitral valve repair (PMVR). METHODS AND RESULTS From March 2014 to July 2015, 186 patients were treated for severe mitral regurgitation with PMVR using the MitraClip system. In 40 patients, oesophago-gastro-duodenoscopy was performed due to symptoms related to the gastrointestinal tract. Based on the procedure duration, patients were classified into group 1 (>60 minutes, n=23) or into group 2 (