Aortic Valve Stenosis Causes Accumulation of Extracellular Hemoglobin and Systemic Endothelial Dysfunction.

BACKGROUND: Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown. METHODS: We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and NO consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system. RESULTS: In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb and plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress. CONCLUSIONS: AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05603520. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01805739.

Roadmap fusion imaging in percutaneous coronary intervention reduces contrast medium exposure irrespective of investigator's experience level.

OBJECTIVES: Dynamic Coronary Roadmap (DCR) is a software tool that creates a real-time dynamic coronary artery overlay on fluoroscopic images. The efficacy of DCR in significantly reducing contrast medium use during percutaneous coronary interventions (PCI) has previously been shown. In this study, we aimed to determine if DCR is equally effective irrespective of the performing investigator's experience level. METHODS: In this sub-analysis of a monocentric, open-label, randomized trial, 130 patients with hemodynamic relevant coronary type A and B lesions were randomized and contrast medium use was conducted with (+) or without (-) DCR software. PCI was randomly allocated and performed by an investigator with high (A) or medium (B) experience level. RESULTS: Overall, contrast medium use was significantly reduced by both investigators in the +DCR group, and Investigator B used significantly less contrast medium with the software than Investigator A. The DCR software was not accompanied by increased radiation exposure for the patients or the teams. On the contrary, dose area product was reduced by both investigators, but was significantly reduced by the highly experienced investigator when using DCR. Fluoroscopy time was not different between investigators. Procedural success was 100%. Serious in-hospital adverse events were not observed. One of Investigator A's patients suffered from post-procedural acute kidney injury in the -DCR group. CONCLUSIONS: DCR significantly reduces contrast medium use during PCI irrespective of investigator's experience level.

Cocoa flavanols improve peakVO2 and exercise capacity in a randomized double blinded clinical trial in healthy elderly people.

Background: Loss of functional capacity is one of the hallmarks in cardiovascular aging. Cocoa flavanols (CF) exert favorable effects on endothelial function, blood pressure, and inflammation. These cardiovascular health markers worsen with increasing age and limit functional exercise capacity. Aim: To investigate the effect of CF on cardiorespiratory-fitness in healthy elderly people. Methods: In a randomized, double-masked, placebo-controlled, parallel-group dietary intervention trial, 68 healthy elderly people (55-79 years, 28 female) received either 500 mg of CF or a nutrient-matched control capsule twice a day for 30 days. Primary endpoint was defined as peak oxygen consumption (VO2) in a cardiopulmonary exercise test (CPET). Secondary endpoints were oxygen pulse (VO2 per heart rate (HR)), resting blood pressure (BP), and resting vascular function. Results: After 30 days of CF intake peakVO2 increased by 190 ml min-1 (95% CI 1-371 ml min-1) and peakVO2 per kg by 2.5 ml (min kg)-1 (95% CI 0.30-4.2 ml (min kg)-1). O2-pulse increased by 1.7 ml (95% CI 0.29-3.2 ml) and max exercise capacity by 9.6 W (95% CI 2.1-17.7 W). CF decreased resting systolic and diastolic BP by 5.4 mmHg (95% CI -10.7 to -0.1 mmHg) and 2.9 mmHg (95% CI -5.5 to -0.4 mmHg), respectively. Flow-mediated vasodilation (FMD) increased by an absolute 1.3% (95% CI 0.76-1.79%) in the CF group. Indexes of pulmonary function were not affected. No changes for primary and secondary endpoints were detected in control. Conclusion: CF substantially improve markers of cardiorespiratory fitness in healthy elderly humans highlighting their potential to preserve cardiovascular health with increasing age.

Cocoa flavanol supplementation preserves early and late radial artery function after transradial catheterization.

Background: The transradial approach for coronary angiography is associated with fewer complications and preferred over the femoral approach. Injury to the radial artery (RA) endothelium elicits intimal hyperplasia, possibly resulting in total occlusion and limb functional decline. Flavanols are known to improve endothelial function. Effects on arterial remodeling after mechanical injury are unknown. Objective: To investigate the effects of cocoa flavanols on (a) intimal hyperplasia and (b) endothelial functional recovery after mechanical vascular wall injury through transradial coronary angiography (TCA). Methods: Primary endpoint in this double-blind, randomized, controlled trial was RA intima-media thickness (IMT) after 6 months follow-up (FU). Secondary endpoints were RA flow-mediated vasodilation (FMD) and fractional diameter change (Fdc). Further luminal diameter and circulating endothelial microparticles (EMP) were assessed. Thirty-six male patients undergoing elective TCA were included. Flavanol or matched placebo supplementation started 7 days prior TCA (cocoa flavanol 1000 mg day-1) for 14 days. Four measurements spanned three periods over 6-moths-FU. Results: TCA induced sustained intimal hyperplasia in the placebo-, but not in the flavanol-group (IMT 0.44 ± 0.01 vs. 0.37 ± 0.01 mm, p = 0.01). FMD decreased after TCA in both groups, but recovered to baseline after 6 months in the flavanol group only. Fdc acutely decreased, EMPs increased in the placebo-, not in the flavanol -group. Luminal diameter remained unchanged in both groups. Conclusion: Peri-interventional cocoa flavanol supplementation prevents long-term intima media thickening and endothelial dysfunction 6 months after TCA opening the perspective for dietary interventions to mitigate endothelial cell damage and intimal hyperplasia after mechanical injury.

Lactate versus Phosphate as Biomarkers to Aid Mechanical Circulatory Support Decisions in Patients with Out-of-Hospital Cardiac Arrest and Return of Spontaneous Circulation.

AIMS: Identifying patients who may benefit from mechanical circulatory support (MCS) after out-of-hospital cardiac arrest (OHCA) and return of spontaneous circulation (ROSC) remains challenging; thus, a search for helpful biomarkers is warranted. We aimed to evaluate phosphate and lactate levels on admission regarding their associations with survival with and without MCS. METHODS: In 224 OHCA patients who achieved ROSC, the initial phosphate and lactate levels were investigated to discriminate in-hospital mortality by receiver operating characteristic (ROC) curves. According to the Youden Index (YI) from the respective ROC, the groups were risk stratified by both biomarkers, and 30-day mortality was analyzed in patients with and without MCS. RESULTS: Within the entire collective, MCS was not associated with a better chance of survival. Both phosphate and lactate level elevations showed good yet comparable discriminations to predict mortality (areas under the curve: 0.80 vs. 0.79, p = 0.74). In patients with initial phosphate values > 2.2 mmol/L (>YI), 30-day mortality within the MCS cohort was lower (HR 2.3, 95% CI: 1.4-3.7; p = 0.0037). In patients with lower phosphate levels and groups stratified by lactate, 30-day mortality was similar in patients with and without MCS. CONCLUSIONS: We found a significant association between survival and MCS therapy in patients with phosphate levels above 2.2 mmol/L (Youden Index), and a similar discrimination of patient overall survival by lactate and phosphate. Prospective studies should assess the possible independent prognostic value of phosphate and its clearance for MCS efficiency.

Platelet pannexin-1 channels modulate neutrophil activation and migration but not the progression of abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a common disease and highly lethal if untreated. The progressive dilatation of the abdominal aorta is accompanied by degradation and remodeling of the vessel wall due to chronic inflammation. Pannexins represent anion-selective channels and play a crucial role in non-vesicular ATP release to amplify paracrine signaling in cells. Thus, pannexins are involved in many (patho-) physiological processes. Recently, Panx1 channels were identified to be significantly involved in abdominal aortic aneurysm formation through endothelial derived Panx1 regulated inflammation and aortic remodeling. In platelets, Panx1 becomes activated following activation of glycoprotein (GP) VI. Since platelets play a role in cardiovascular diseases including abdominal aortic aneurysm, we analyzed the contribution of platelet Panx1 in the progression of abdominal aortic aneurysm. We detected enhanced Panx1 plasma levels in abdominal aortic aneurysm patients. In experimental abdominal aortic aneurysm using the pancreatic porcine elastase (PPE) mouse model, a major contribution of platelet Panx1 channels in platelet activation, pro-coagulant activity of platelets and platelet-mediated inflammation has been detected. In detail, platelets are important for the migration of neutrophils into the aortic wall induced by direct cell interaction and by activation of endothelial cells. Decreased platelet activation and inflammation did not affect ECM remodeling or wall thickness in platelet-specific Panx1 knock-out mice following PPE surgery. Thus, aortic diameter expansion at different time points after elastase infusion of the aortic wall was unaltered in platelet-specific Panx1 deficient mice suggesting that the modulation of inflammation alone does not affect abdominal aortic aneurysm formation and progression. In conclusion, our data strongly supports the role of platelets in inflammatory responses in abdominal aortic aneurysm via Panx1 channels and adds important knowledge about the significance of platelets in abdominal aortic aneurysm pathology important for the establishment of an anti-platelet therapy for abdominal aortic aneurysm patients.

Elevated Initial Serum Phosphate Levels Predict Higher Mortality and Impaired Neurological Outcome in Cardiac Arrest Patients with Return of Spontaneous Circulation.

Purpose: Although a moderate proportion of cardiac arrest (CA) patients achieve a return of spontaneous circulation (ROSC), few survive to discharge, mostly with poor neurological development. As serum phosphate levels were described as elevated after cardiopulmonary resuscitation (CPR), we asked whether these elevations would predict a higher risk of mortality and impaired neurological outcome in CA patients following ROSC. Methods: Initial serum phosphate levels, survival, and neurologic status at discharge of 488 non-traumatic CA patients treated at a single German hospital after achieving ROSC were analyzed. The cut-off value of phosphate for mortality prediction was determined using the receiver operator characteristic (ROC) curve, and patients were divided accordingly for comparison. Results were validated by analyzing phosphate levels in a multi-centric cohort containing 3299 CA patients from the eICU database of the United States. Results: In the German cohort, ROC analysis showed a 90% specificity for phosphate levels >2.7 mmol/L to predict mortality (AUC: 0.76, p < 0.0001), and phosphate level elevations were associated with higher in-hospital mortality (crude odds ratio 3.04, 95% CI 2.32 to 4.08). Patients with initial phosphate levels >2.7 mmol/L had significantly higher mortality in both analyzed collectives (p < 0.0001). Similarly, patients from the German cohort who initially had higher phosphate levels also showed a higher proportion of impaired neurological status at discharge and morphological signs of brain injury. Conclusions: In CA patients following ROSC, initial serum phosphate levels >2.7 mmol/L predict higher mortality and impaired neurological outcome. Our data suggests that phosphate determination might improve the preciseness of the overall and neurologic prognostication in patients after CPR following ROSC.

Toll-like receptor-3 contributes to the development of aortic valve stenosis.

Aortic valve stenosis (AS) development is driven by distinct molecular and cellular mechanisms which include inflammatory pathways. Toll-like-receptor-3 (TLR3) is a lysosomal pattern-recognition receptor that binds double-stranded RNA and promotes pro-inflammatory cellular responses. In recent years, TLR3 has emerged as a major regulator of vascular inflammation. The exact role of TLR3 in the development of AS has not been investigated. Isolated human valvular interstitial cells (VICs) were stimulated with the TLR3-agonist polyIC and the resulting pro-inflammatory and pro-osteogenic response measured. Severe AS was induced in wildtype- and TLR3-/- mice via mechanical injury of the aortic valve with a coronary springwire. TLR3 activation was achieved by polyIC injection every 24 h after wire injury, while TLR3 inhibition was realized using Compound 4a (C4a) every 48 h after surgery. Endothelial mesenchymal transition (EndoMT) of human valvular endothelial cells (VECs) was assessed after polyIC stimulation. Stimulation of human VICs with polyIC promoted a strong inflammatory and pro-osteogenic reaction. Similarly, injection of polyIC marginally increased AS development in mice after wire injury. AS induction was significantly decreased in TLR3-/- mice, confirming the role of endogenous TLR3 ligands in AS pathology. Pharmacological inhibition of TLR3 with C4a not only prevented the upregulation of inflammatory cytokines and osteogenic markers in VICs, and EndoMT in VECs, but also significantly abolished the development of AS in vivo. Endogenous TLR3 activation significantly contributes to AS development in mice. Pharmacological inhibition of TLR3 with C4a prevented AS formation. Therefore, targeting TLR3 may be a viable treatment option.

Multi-Slice Computed Tomography Analysis in Patients Undergoing Transcatheter Aortic Valve Replacement - Impact of Workflows on Measurement of Virtual Aortic Annulus and Valve Size.

Exact and reliable measurements of anatomical dimensions in pre-procedural multi-slice computed tomography (MSCT) scans are crucial for optimal valve sizing and clinical results of transcatheter aortic valve replacement (TAVR). This study aimed to investigate interrater reliability between routinely used workflows for pre-procedural analysis. MSCT scans of 329 patients scheduled for TAVR were analyzed using both a 3mensio and SECTRA IDS7 platform. The results were retrospectively compared using the intraclass correlation coefficient, revealing excellent correlation in the analysis of simple diameters and poor correlation in the assessment of more complex structures with impact on calculated valve size.

Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis.

Aortic valve stenosis (AS) is the most frequent valve disease with relevant prognostic impact. Experimental model systems for AS are scarce and comprehensive imaging techniques to simultaneously quantify function and morphology in disease progression are lacking. Therefore, we refined an acute murine AS model to closely mimic human disease characteristics and developed a high-resolution magnetic resonance imaging (MRI) approach for simultaneous in-depth analysis of valvular, myocardial as well as aortic morphology/pathophysiology to identify early changes in tissue texture and critical transition points in the adaptive process to AS. AS was induced by wire injury of the aortic valve. Four weeks after surgery, cine loops, velocity, and relaxometry maps were acquired at 9.4 T to monitor structural/functional alterations in valve, aorta, and left ventricle (LV). In vivo MRI data were subsequently validated by histology and compared to echocardiography. AS mice exhibited impaired valve opening accompanied by significant valve thickening due to fibrotic remodelling. While control mice showed bell-shaped flow profiles, AS resulted not only in higher peak flow velocities, but also in fragmented turbulent flow patterns associated with enhanced circumferential strain and an increase in wall thickness of the aortic root. AS mice presented with a mild hypertrophy but unaffected global LV function. Cardiac MR relaxometry revealed reduced values for both T1 and T2 in AS reflecting subtle myocardial tissue remodelling with early alterations in mitochondrial function in response to the enhanced afterload. Concomitantly, incipient impairments of coronary flow reserve and myocardial tissue integrity get apparent accompanied by early troponin release. With this, we identified a premature transition point with still compensated cardiac function but beginning textural changes. This will allow interventional studies to explore early disease pathophysiology and novel therapeutic targets.

Structured Allocation of Transcatheter Aortic Valve Replacement Patients during Coronavirus Disease 2019 Pandemic: Impact on Patient Selection and Clinical Results.

Due to shortages of medical resources during the Coronavirus Disease 2019 (COVID-19) pandemic, an allocation algorithm for Transcatheter Aortic Valve Replacement (TAVR) was established. We investigated the impact on patient selection and procedural results. In total, 456 TAVR patients before (pre-COVID-19 group) and 456 TAVR patients after (COVID-19 group) the implementation of our allocation algorithm were compared. Concerning patient characteristics, the COVID-19 group revealed a higher rate of cardiac decompensations/cardiogenic shocks (10.5% vs. 1.3%; p < 0.001), severe angina pectoris (Canadian Cardiovascular Society (CCS) II, III and IV: 18.7% vs. 11.8%; p = 0.004), troponin elevation (>14 ng/L: 84.9% vs. 77%; p = 0.003) and reduced left ventricular ejection fraction (LVEF) (<45%: 18.9% vs. 12%; p = 0.006). Referring to procedural characteristics, more predilatations (46.3% vs. 35.1%; p = 0.001) and a longer procedural time (80.2 min (+/−29.4) vs. 66.9 min (+/−17.5); p < 0.001) were observed. The success rate was evenly high; no differences in safety parameters were reported. Examining the utilization of hospital resources, the COVID-19 group showed a shorter in-hospital stay (8.4 days (+/−5.9) vs. 9.5 days (+/−9.33); p = 0.041) and fewer TAVR patients were treated per month (39 (+/−4.55) vs. 46.11 (+/−7.57); p = 0.03). Our allocation algorithm supported prioritization of sicker patients with similar efficient and safe TAVR procedures. In-hospital stay could be shortened.

[Clinical Advances in Aortic Diseases: from Aortic Valve to Bifurcation]. / Erkrankungen der Aorta: von der Aortenklappe bis zur Aortenbifurkation.

There is growing understanding to recognize the aorta as complex system and treat aortic diseases in an integrated fashion.The indication for interventional aortic valve replacement (TAVR) comprises patients with moderate and high perioperative risk and symptomatic, high grade aortic valve stenosis. In contrast "low risk" patients receive conventional therapy. Ongoing randomised trials analyse the expansion of indication towards low risk patients for interventional approaches. A final rating is owing, but first data support the assumption that both therapeutic options may be equivalent. Moreover, the interventional therapy of low flow, low gradient aortic valve stenosis has been revalued and interventional valve-in-valve therapy has been integrated into clinical routine as invidualised decision of the heart team.Aortic diseases include several entities which require specialised diagnostic and therapeutic tools. Studies to evaluate evidence of follow up options need to be performed in future to enable for surveillance tailored to suit medical need.

Graded murine wire-induced aortic valve stenosis model mimics human functional and morphological disease phenotype.

Aortic valve stenosis (AS) is the most common valve disease requiring therapeutic intervention. Even though the incidence of AS has been continuously rising and AS is associated with significant morbidity and mortality, to date, no medical treatments have been identified that can modify disease progression. This unmet medical need is likely attributed to an incomplete understanding of the molecular mechanism driving disease development. To investigate the pathophysiology leading to AS, reliable and reproducible animal models that mimic human pathophysiology are needed. We have tested and expanded the protocols of a wire-injury induced AS mouse model. For this model, coronary wires were used to apply shear stress to the aortic valve cusps with increasing intensity. These protocols allowed distinction of mild, moderate and severe wire-injury. Upon moderate or severe injury, AS developed with a significant increase in aortic valve peak blood flow velocity. While moderate injury promoted solitary AS, severe-injury induced mixed aortic valve disease with concomitant mild to moderate aortic regurgitation. The changes in aortic valve function were reflected by dilation and hypertrophy of the left ventricle, as well as a decreased left ventricular ejection fraction. Histological analysis revealed the classic hallmarks of human disease with aortic valve thickening, increased macrophage infiltration, fibrosis and calcification. This new mouse model of AS promotes functional and morphological changes similar to moderate and severe human AS. It can be used to investigate the pathomechanisms contributing to AS development and to test novel therapeutic strategies.

Cost-comparison of third generation transcatheter aortic valve implantation (TAVI) devices in the German Health Care System.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has a substantial impact on daily cardiovascular care delivery based on issues such as cost effectiveness and economic value within a restricted health care budget. Until now, potential financial benefits of third generation valve models have not been evaluated in a real-world setting. METHODS AND RESULTS: We identified 204 eligible patients (Jan 2014-Sep 2016) who either received the balloon-expandable Edwards Sapien 3 (ES3) or the self-expandable Medtronic Evolut R (MER). Baseline information, procedural characteristics, 30-day outcome as well as in-hospital costs and reimbursement were collected and analyzed. The major cost driver was initial valve-kit costs with a significantly higher amount in the ES3 group, which was set at 0 with the lower price (ES3/MER: +4390.0€â€¯±â€¯3.807.0 vs. 0.0€â€¯±â€¯734.1; p < 0.01). However, initial valve-kit costs were balanced by additional material costs in the MER cohort. Overall costs did not differ significantly between valve models (ES3/MER: x + 13.808.0€â€¯±â€¯5.595.0 vs. x + 10.681.0€â€¯±â€¯4.518.0; p = 0.6885) and reimbursement was moderate (ES3/MER: 1.649.7€ vs. 4776.7€). CONCLUSION: Quality, success rate, and costs were comparable between third generation devices. Initial valve-kit costs were significantly higher in the ES3 group, whereas overall costs did not significantly differ between the two valve types.

Balloon Valvuloplasty Followed by Transcatheter Aortic Valve Implantation as a Staged Procedure in Patients With Low-Flow Low-Gradient Aortic Stenosis.

OBJECTIVE: Balloon aortic valvuloplasty (BAV) as a bridge to transcatheter aortic valve implantation (TAVI) is a well-established treatment option in patients who are in a critical state or who suffer from underlying comorbidities that disguise the severity of aortic stenosis (AS). If convalescence is achieved, TAVI can be performed with good results in high-gradient aortic stenosis (HG-AS) patients. Whether this approach is safe and effective in low-flow low-gradient aortic stenosis (LFLG-AS) has not been analyzed; therefore, we investigated whether BAV followed by TAVI as a staged procedure is an effective treatment option in patients with LFLG-AS. METHODS: Patients with severe AS who received BAV followed by staged TAVI were identified. Baseline data, periprocedural and postprocedural information, echocardiographic data, and follow-up data were collected. The patient population was divided into LFLG-AS and HG-AS groups. RESULTS: From July 2009 until September 2017, we identified 38 eligible patients (16 LFLG-AS and 22 HG-AS). Log EuroScore I (51.8 ± 20.9% LFLG-AS vs 33.7 ± 19.1% HG-AS; P<.01) differed significantly between groups, as did baseline echocardiographic data that were used to categorize groups. BAV and staged TAVI were carried out 100% successfully with comparable results. Instant symptom relief and pressure gradient reduction were accomplished after both procedures. Thirty-day mortality rates (0% LFLG-AS vs 9% HG-AS; P=.21) and 1-year mortality rates (18.8% LFLG-AS vs 27.2% HG-AS; P=.54) did not differ between groups. CONCLUSION: BAV followed by staged TAVI is a safe and effective treatment option in sick or questionable candidates, irrespective whether LFLG-AS or HG-AS is present.

The Latest Evolution of the Medtronic CoreValve System in the Era of Transcatheter Aortic Valve Replacement: Matched Comparison of the Evolut PRO and Evolut R.

OBJECTIVES: The aim of this study was to investigate the hemodynamic and clinical performance of the Evolut PRO compared with its direct predecessor, the Evolut R. BACKGROUND: Recently, the newest commercially available generation of the self-expandable Medtronic CoreValve prosthesis, the CoreValve Evolut PRO, was introduced to the market. This prosthesis is based on the previous Evolut R model and specifically designed to mitigate paravalvular leakage. Because of the design changes, the Evolut PRO needs a larger sheath size (16-F vs. 14-F). METHODS: Patients receiving either the Evolut R (n = 148) or the Evolut PRO (n = 74) from September 2015 to January 2018 were compared in a 2:1 fashion after propensity score matching. Baseline characteristics, cardiovascular imaging, and pre- and periprocedural outcomes were prospectively collected and assessed. RESULTS: Both cohorts represent a high-risk, real-world collective with increased perioperative mortality risk (logistic European System for Cardiac Operative Risk Evaluation score, Evolut R vs. Evolut PRO: 24.7 ± 13.7% vs. 25.1 ± 12.5%; p = 0.881). Procedural success was 100%, and the mean transvalvular pressure gradient was substantially reduced (Evolut R vs. Evolut PRO: 7.9 ± 3.9 mm Hg vs. 7.5 ± 3.5 mm Hg; p = 0.348). Mild paravalvular leakage was observed in 16.2% of Evolut R patients and in 14.9% of Evolut PRO patients (p = 0.794). In the Evolut R group, moderate aortic regurgitation was documented in 2 patients (Evolut R vs. Evolut PRO: 1.4% vs. 0%; p = 1.000). No differences regarding clinical parameters, such as major bleeding events (Evolut R vs. Evolut PRO: 1.4% vs.1.3%; p = 0.868) and vascular complications were observed. CONCLUSIONS: Both prostheses show excellent hemodynamic performance with a low incidence of paravalvular leakage and comparable clinical outcomes.

CD73 on T Cells Orchestrates Cardiac Wound Healing After Myocardial Infarction by Purinergic Metabolic Reprogramming.

BACKGROUND: T cells are required for proper healing after myocardial infarction. The mechanism of their beneficial action, however, is unknown. The proinflammatory danger signal ATP, released from damaged cells, is degraded by the ectonucleotidases CD39 and CD73 to the anti-inflammatory mediator adenosine. Here, we investigate the contribution of CD73-derived adenosine produced by T cells to cardiac remodeling after ischemia/reperfusion and define its mechanism of action. METHODS: Myocardial ischemia (50 minutes followed by reperfusion) was induced in global CD73-/- and CD4-CD73-/- mice. Tissue injury, T-cell purinergic signaling, cytokines, and cardiac function (magnetic resonance tomography at 9.4 T over 4 weeks) were analyzed. RESULTS: Changes in functional parameters of CD4-CD73-/- mice were identical to those in global CD73 knockouts (KOs). T cells infiltrating the injured heart significantly upregulated at the gene (quantitative polymerase chain reaction) and protein (enzymatic activity) levels critical transporters and enzymes (connexin43, connexin37, pannexin-1, equilibrative nucleoside transporter 1, CD39, CD73, ecto-nucleotide pyrophosphatase/phosphodiesterases 1 and 3, CD157, CD38) for the accelerated release and hydrolysis of ATP, cAMP, AMP, and NAD to adenosine. It is surprising that a lack of CD39 on T cells (from CD39-/- mice) did not alter ATP hydrolysis and very likely involves pyrophosphatases (ecto-nucleotide pyrophosphatase/phosphodiesterases 1 and 3). Circulating T cells predominantly expressed A2a receptor (A2aR) transcripts. After myocardial infarction, A2b receptor (A2bR) transcription was induced in both T cells and myeloid cells in the heart. Thus, A2aR and A2bR signaling may contribute to myocardial responses after myocardial infarction. In the case of T cells, this was associated with an accelerated secretion of proinflammatory and profibrotic cytokines (interleukin-2, interferon-γ, and interleukin-17) when CD73 was lacking. Cytokine production by T cells from peripheral lymph nodes was inhibited by A2aR activation (CGS-21680). The A2bR agonist BAY 60-6583 showed off-target effects. The adenosine receptor agonist NECA inhibited interferon-γ and stimulated interleukin-6 production, each of which was antagonized by a specific A2bR antagonist (PSB-603). CONCLUSIONS: This work demonstrates that CD73 on T cells plays a crucial role in the cardiac wound healing process after myocardial infarction. The underlying mechanism involves a profound increase in the hydrolysis of ATP/NAD and AMP, resulting primarily from the upregulation of pyrophosphatases and CD73. We also define A2bR/A2aR-mediated autacoid feedback inhibition of proinflammatory/profibrotic cytokines by T cell-derived CD73.

Adenosine Formed by CD73 on T Cells Inhibits Cardiac Inflammation and Fibrosis and Preserves Contractile Function in Transverse Aortic Constriction-Induced Heart Failure.

BACKGROUND: Structural damage during heart failure development leads to increased infiltration of leukocytes. Because purinergic signaling on immune cells may impact on the inflammatory response, we evaluated the role of ecto-5'-nucleotidase (CD73) on the development of heart failure after transverse aortic constriction (TAC) using global and T-cell-specific CD73-/- mice. METHODS AND RESULTS: Leukocytes infiltrating the failing heart were analyzed by a multistep enzymatic procedure over a period of 16 weeks using fluorescence-activated cell sorting. TAC significantly enhanced the infiltration of leukocytes, especially T cells. The fraction of CD73 expressing cells increased over time exclusively on cytotoxic T cells, T-helper cells, and regulatory T cells. Cardiac function significantly declined in T-cell-specific CD4-Cre+/-CD73flox/flox mice identical to that observed in global CD73 mutants and was associated with enhanced fibrosis (collagen, laminin, vimentin, periostin). Expression analysis by quantitative reverse transcription polymerase chain reaction of extracellular purine degrading enzymes and P1 and P2 receptors on T cells isolated from the injured heart revealed profound upregulation of the enzymatic machinery for hydrolysis of extracellular adenosine triphosphate and nicotinamide adenine dinucleotide, both pathways converging in the formation of AMP and adenosine via CD73. Among the P1 receptors, only the A2a receptor was significantly upregulated after TAC. T cells isolated from TAC-treated hearts show enhanced production of proinflammatory cytokines (interleukin-3, interleukin-6, interleukin-13, interleukin-17, macrophage inflammatory proteins-1α, and macrophage inflammatory proteins-1ß) when CD73 was lacking. CONCLUSIONS: Our data provide first evidence that CD73 on T cells plays an important anti-inflammatory role in TAC-induced heart failure, which is associated with antifibrotic activity and reduced production of proinflammatory cytokines most likely by activation of the adenosine A2a receptor.

Epicardium-Derived Cells Formed After Myocardial Injury Display Phagocytic Activity Permitting In Vivo Labeling and Tracking.

UNLABELLED: Epicardium-derived cells (EPDCs) cover the heart surface and can function as a source of both progenitor cells and trophic factors for cardiac repair. Currently, EPDCs cannot be conveniently labeled in vivo to permit imaging and cell tracking. EPDCs formed after myocardial infarction (MI) preferentially take up a perfluorocarbon-containing nanoemulsion (PFC-NE; 130 ± 32 nm) injected 3 days after injury, as measured by (19)F-magnetic resonance imaging ((19)F-MRI). Flow cytometry, immune electron microscopy, and green fluorescent protein (GFP)-transgenic rats (only immune cells, but not epicardial cells, are GFP(+)) demonstrated that PFC-containing EPDCs are nonhematopoietic (CD45(-)/CD11b(-)) but stain positive for markers of mesenchymal stem cells such as platelet-derived growth factor receptor α (PDGFR-α) CD73, CD105, and CD90. When rhodamine-coupled PFC-NE was used, we found that ρ(+) vessel-like structures formed within the infarcted myocardium, comprising approximately 10% of all large vessels positive for smooth muscle actin (SM-actin). The epicardial cell layer, positive for Wilms' tumor 1 (WT-1), PDGFR-α, or KI-67, was shown to be well capillarized (293 ± 78 capillaries per mm(2)), including fenestrated endothelium. Freshly isolated EPDCs were positive for WT-1, GATA-4, KI-67, and FLK-1 (75%), PDGFR-α (50%), and SM-actin (28%) and also exhibited a high capacity for nanoparticle and cell debris uptake. This study demonstrates that EPDCs formed after MI display strong endocytic activity to take up i.v.-injected labeled nanoemulsions. This feature permitted in vivo labeling and tracking of EPDCs, demonstrating their role in myo- and vasculogenesis. The newly discovered endocytic activity permits in vivo imaging of EPDCs with (19)F-MRI and may be used for the liposomal delivery of substances to further study their reparative potential. SIGNIFICANCE: The present study reports that epicardium-derived cells (EPDCs) formed after myocardial infarction can specifically endocytose nanoparticles in vivo and in vitro. This novel feature permitted in vivo targeting of EPDCs with either a perfluorocarbon-containing or rhodamine-conjugated nanoemulsion to track migration and fate decision of EPDC with (19)F-magnetic resonance imaging and fluorescence microscopy. The liposomal nanoemulsions used in the present study may be useful in the future as a nanomedical device for the delivery of substances to direct cell fate of EPDCs.

Noninvasive Imaging of Early Venous Thrombosis by 19F Magnetic Resonance Imaging With Targeted Perfluorocarbon Nanoemulsions.

BACKGROUND: Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques. METHODS AND RESULTS: Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free 19F magnetic resonance imaging, together with α2-antiplasmin peptide (α2AP)-targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter<0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching 1H and 19F magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71±22 and 17±5, respectively). Furthermore, α2AP-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of α2AP-PFCs>60 minutes after thrombus induction no longer resulted in detectable 19F magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, α2AP-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention. CONCLUSIONS: Our results demonstrate that 1H/19F magnetic resonance imaging, together with α2AP-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo 19F magnetic resonance imaging.