Coronary microthrombi in the failing human heart: the role of von Willebrand factor and PECAM-1.

The recognition of microthrombi in the heart microcirculation has recently emerged from studies in COVID-19 decedents. The present study investigated the ultrastructure of coronary microthrombi in heart failure (HF) due to cardiomyopathies that are unrelated to COVID-19 infection. In addition, we have investigated the role of von Willebrand factor (VWF) and PECAM-1 in microthrombus formation. We used electron microscopy to investigate the occurrence of microthrombi in patients with HF due to dilated (DCM, n = 7), inflammatory (MYO, n = 6) and ischemic (ICM, n = 7) cardiomyopathy and 4 control patients. VWF and PECAM-1 was studied by quantitative immunohistochemistry and Western blot. In comparison to control, the number of microthrombi was increased 7-9 times in HF. This was associated with a 3.5-fold increase in the number of Weibel-Palade bodies (WPb) in DCM and MYO compared to control. A fivefold increase in WPb in ICM was significantly different from control, DCM and MYO. In Western blot, VWF was increased twofold in DCM and MYO, and more than threefold in ICM. The difference between ICM and DCM and MYO was statistically significant. These results were confirmed by quantitative immunohistochemistry. Compared to control, PECAM-1 was by approximatively threefold increased in all groups of patients. This is the first study to demonstrate the occurrence of microthrombi in the failing human heart. The occurrence of microthrombi is associated with increased expression of VWF and the number of WPb, being more pronounced in ICM. These changes are likely not compensated by increases in PECAM-1 expression.

Endothelialization and Inflammatory Reactions After Intracardiac Device Implantation.

BACKGROUND: Due to the advances in catheter-based interventional techniques, a wide range of heart diseases can now be treated with a purely interventional approach. Little is yet known regarding biological effects at the intracardiac implantation site or the effects on endothelialization and vascular inflammation in an in vivo environment. Detailed knowledge of ongoing vascular response, the process of endothelialization, and possible systemic inflammatory reactions after implantation is crucial for the clinical routine, since implants usually remain in the body for a lifetime. METHODS: For this narrative review, we conducted an extensive profound PubMed analysis of the current literature on the endothelialization processes of intracardially implanted devices, such as persistent foramen ovale (PFO) occluders, atrial septal defect (ASD) occluders, left atrial appendage (LAA) occluders, transcatheter aortic valve implantations (TAVIs), and leadless pacemakers. Additionally, the known biological activities of common metallic and synthetic components of intracardiac devices in an "in vivo" setting have been evaluated. RESULTS: Nitinol, an alloy of nickel and titanium, is by far the most commonly used material found in intracardiac devices. Although allergies to both components are known, implantation can be performed safely in the vast majority of patients. Depending on the device used, endothelialization can be expected within a time frame of 3-6 months. For those patients with a known allergy, gold coating may be considered as a viable alternative. CONCLUSION: Based on our analysis, we conclude that the vast majority of devices are made of a material that is both safe to implant and nontoxic in long-term treatment according to the current knowledge. The literature on the respective duration of endothelialization of individual devices however is highly divergent.

Disease-specific characteristics of vascular cell adhesion molecule-1 levels in patients with peripheral artery disease.

Peripheral arterial disease (PAD) is one of the most common manifestations of systemic atherosclerosis. The prevalence of unrecognized PAD is high, leading to a lack of opportunity to detect subjects at a high risk for cardiovascular events. Inflammatory processes play an important role in the disease initiation as well as in the disease progression. Vascular cell adhesion molecule 1 (VCAM-1), a biomarker of endothelial dysfunction, appears to be an important mediator in inflammatory processes. Therefore, we hypothesized that in patients with PAD, circulating VCAM-1 might be elevated due to its function in mediating adhesion of immune cells to the vascular endothelium in the process of endothelial dysfunction and inflammation, and, therefore, applicable as a diagnostic biomarker. A total of 126 non-consecutive patients were enrolled in this study, of whom 51 patients had typical clinical manifestations of PAD and as controls 75 patients with no history of PAD or cardiovascular disease. All serum samples were obtained either during hospitalization or during out-patient visits and analyzed for VCAM-1 by the ELISA. Compared with controls, median levels of VCAM-1 were significantly elevated in patients suffering from PAD (953 vs. 1352 pg/ml; p < 0.001). Furthermore, VCAM-1 appeared to be highly discriminative for the detection of PAD (AUC = 0.76; CI 0.67-0.83). We could not observe dynamics related to increasing disease stages according to Rutherford classes in patients with apparent PAD. VCAM-1 was shown to be a potential discriminator and biomarker for the severity of systemic atherosclerosis. In a logistic regression analysis, VCAM-1 was robustly associated with the diagnosis of PAD, even after correction for clinically relevant cofounders (namely age, arterial hypertension, diabetes and LDL levels). Thusly, VCAM-1 might serve as a biomarker for PAD screening and detection.

Economic assessment of traditional surgical valve replacement versus use of transfemoral intervention in degenerative aortic stenosis.

INTRODUCTION: The aim of this study was to provide an economic assessment of interventional vs. surgical aortic valve replacement in the context of cost-effectiveness. Aortic stenosis represents the most common form of degenerative valvular heart diseases. As life expectancy increases, an even emerging prevalence is expected. Over decades, surgical replacement was considered as the method of choice. Up to one third of the patients were not eligible for surgery, as their estimated peri-operative risk was too high. In the early 2000s a catheter-based technique has been developed, being an alternative treatment option for patients, considered to be inoperable. EVIDENCE ACQUISITION: A systematic analysis of current literature was performed from September 2018 to December 2018. All suitable data in the field was obtained from Pubmed and Google/Google scholar. The search terms "TAVI AND costs," "TAVR and costs" and "aortic valve replacement AND costs" was entered in the search field, showing an overall amount of 317 publications. In a next step all obtained publications were screened by expert hand selection. EVIDENCE SYNTHESIS: Recently the Food and Drug Association (FDA) approved transcatheter aortic valve replacement (TAVR) in the low-risk setting. Nevertheless, concerns on the higher price remain. We performed an analysis of current literature on aortic stenosis and economic aspects. Out of 322 screened publications, 7 studies were found eligible by expert hand selection. Based on the predefined payment readiness of the analyzed healthcare system, TAVR appeared to have a slightly better cost effectiveness. Initial results within the early era seemed to be inconsistent. Recent publications showed, TAVR might be of more cost effectiveness when using the newest generation devices and a profound clinical experience is guaranteed. CONCLUSIONS: We assume, that TAVR will not only be the method of choice for the treatment of aortic stenosis in many patients. As the valves are getting cheaper, TAVR might even be superior to conventional heart surgery from an economic point of view.

How low is "low-flow" in aortic stenosis? A retrospective analysis of patients with true low-flow/low-gradient aortic stenosis undergoing TAVI.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a valuable treatment option for patients with reduced left ventricular ejection fraction (LVEF) and low-flow/low-gradient (LF/LG) aortic stenosis (AS). According to current literature, the presence of severe AS is unlikely in case of severely reduced LVEF and mean pressure gradient (meanPG) below 30 mmHg. However, a considerable number of patients presenting with typical clinical symptoms of severe AS, show gradients below 30 mmHg. We hypothesized, that these patients undergoing TAVI do have a measurable clinical benefit and an improved LVEF. METHODS: In this single center retrospective cohort study, data from 1199 patients undergoing TAVI between 2013 and 2017 was analyzed. A 6-month follow-up was performed to assess changes in NT-proBNP, NYHA-class, and LVEF. RESULTS: Thirty patients presented with LVEF<35%, an aortic valve area (AVA<1 cm2), and a meanPG below 30 mmHg. Mean logistic EuroSCORE II was 24.05±10.9. Most patients (56%) showed improved NYHA-class upon follow-up. NT-proBNP-levels decreased from 3.901 pg/mL IQR 10.880 to 1.491 pg/mL IQR 2.245 (P<0.001). LVEF increased from 30% IQR 6.25 to 40% IQR 15 (P<0.001). CONCLUSIONS: Based on our findings TAVI represents a valuable treatment option even in patients with LF/LG AS and PGmean below 30mmHg.

Emerging trends in cardiovascular research: HFpEF in the spotlight. A bibliometric analysis of the years 2009-2016.

INTRODUCTION: Up to 50% of patients suffering from acute decompensated heart failure show normal or slightly reduced left ventricular ejection fraction (LVEF). This syndrome, which is known as heart failure with preserved ejection fraction (HFpEF) is associated with increasing age. Epidemiological studies could portrait an increasing importance and an even emerging prevalence in the past decades. Still, there is currently no evidenced based medical treatment option available. Our aims were to identify upcoming trends and emerging concepts and to point out important centers in the global research of HFpEF. EVIDENCE ACQUISITION: We performed a bibliometric study on current science in the field of HFpEF to identify study characteristics, impact factors and the countries of origin of basic and clinical studies that were published within the years 2009 to 2016. We further prepared density equalizing maps for visualization of the obtained data. EVIDENCE SYNTHESIS: A total of 5413 studies was screened, of which 794 were found eligible. The scientific output in clinical studies rose from 25 in 2009 to 165 in 2016. Most of the publications had a clinical topic, followed by studies on new imaging techniques. Basic research trials were by far beyond. The USA, Japan and Germany were identified as the most important national contributors to global scientific output. CONCLUSIONS: This first bibliometric study in the field of HFpEF shows a substantial increase of research within the last decade, mainly in the USA, Japan, and continental Europe. As an ongoing therapeutic trend in this field, we identified RAAS-blockade and 5-phosphodiesterase-inhibition.

Endovascular treatment of superior vena cava syndrome by percutaneous venoplasty.

Thrombosis of the superior vena cava leads to obstruction of venous outflow of the head and upper extremities and causes severe clinical symptoms. The management of SVC syndrome depends on aetiology and acuity at clinical presentation and ranges from conservative medical treatment to bypass surgery. Endovascular treatment can provide rapid relief of symptoms and substantial clinical improvement independent of aetiology. We report a case of successful interventional treatment in a patient with catheter-induced SVC thrombosis and present a review of the literature.

Effect of intra-aortic balloon pump support on microcirculation during high-risk percutaneous intervention.

BACKGROUND: Intra-aortic balloon counter-pulsation (IABP) is recommended for hemodynamic support in cardiogenic shock. In addition, it can be applied during high-risk percutaneous interventions (PCI). While IABP support improves microflow in cardiogenic shock, its effect in hemodynamically stable patients is still unclear. We, therefore, sought to evaluate the effect of IABP treatment on microflow in hemodynamically stable patients undergoing elective high-risk PCI. METHODS: In six patients with >50% left main stenosis, microflow was evaluated according to current guidelines, using side-stream dark-field microscopy, visualizing microcirculatory vessels without using fluorescent dyes. Microflow was analyzed separately for each vessel category (diameter: 10-25microm and 26-50microm), using a semiquantitative system (0= no flow; 1= intermittent flow; 2= sluggish flow; 3= continuous flow) by a trained investigator. Steady state recordings and additional recordings twenty seconds after discontinuation of the electively implanted IABP were acquired. RESULTS: Microflow in vessel categories 10-25microm and 26-50microm increased in this group of hemodynamically stable patients on use of IABP. Microflow decreased from 2.73 + or - 0.39 (p=0.052; 26-50microm: 2.88 + or - 0.20, p=0.008) to 2.22 + or - 0.23 (2.18 + or - 0.45) after stopping the IABP and increased to 2.90 + or - 0.14 (p=0.009; 2.85 + or - 0.28, p=0.009) after restart of the IABP. CONCLUSIONS: Circulatory support with IABP increases microcirculatory flow in the smallest vessels of the sublingual mucosa. Our data support the hypothesis that intra-aortic balloon counter-pulsation increases coronary and microvascular perfusion, thus, improving microcirculation even in hemodynamically stable patients. The use of IABP may increase safety of complex PCI and decrease the risk of deleterious complications.

Effect of mechanical ventilation on microvascular perfusion in critical care patients.

PURPOSE: Microvascular perfusion, pivotal for adequate tissue oxygenation is potentially linked to outcome in critical care therapy. Mechanical ventilation (MV) and positive end-expiratory pressure (PEEP) as standard concepts of respiratory management are known to have deleterious effects on regional organ perfusion especially in the splanchnic area. As these effects have been attributed to different physiologic mechanisms, the purpose of this study was to investigate the effect of positive pressure ventilation on extra-abdominal tissue perfusion in non-surgical intensive care patients. METHODS: Sublingual microcirculation was evaluated in 46 severely ill patients (group 1: n=26 requiring MV and PEEP; group 2: n=20 spontaneous breathing) admitted to the intensive care unit using sidestream darkfield intravitalmicroscopy. According to current guidelines, sublingual vessels were categorized by means of size and flow in semi-quantitative categories determining microvascular flow index (MFI). Total microvascular flow index (TMFI) was calculated for each patient as mean value of flow in all vessel categories. RESULTS: No significant difference was observed between both groups in microvascular flow index in each vessel category and in total microvascular flow index. Patients requiring mechanical ventilation presented with more comorbidities and higher acuity of illness scores resulting in a higher ICU mortality, which however was not accompanied by microcirculatory differences at the time of measurement. CONCLUSION: Mechanical ventilation and PEEP have no general deleterious effects on microvascular perfusion of the sublingual mucosa. However, further clinical studies are required to investigate potential effects of higher levels of ventilation pressure or PEEP on microvascular perfusion.

The Occlutech Figulla PFO and ASD occluder: a new nitinol wire mesh device for closure of atrial septal defects.

BACKGROUND: We investigated the safety, feasibility and efficacy of the Occlutech devices for patent foramen ovale (PFO) and atrial septal defect (ASD) closure in a prospective trial. METHODS: The retention discs of the PFO device (23 x 25 mm, 27 x 30 mm) are connected by a 3 mm waist in the center with only one right atrial side central pin. The left atrial disc is produced either with a single or double flat layer, which allows a significant reduction of meshwork material. The ASD occluder (6-40 mm, 3 mm increments) has only one central pin on the right atrial side. Indications for closure included cryptogenic stroke with evidence of a PFO on transesophageal echocardiography (TEE) or an ASD II. The devices were implanted in 29 patients with PFO and in 12 patients with ASD II (fluoroscopy and TEE). An echocardiographic follow-up examination was performed after 1, 2 and 6 months. RESULTS: The devices were successfully implanted in all 41 patients. There were no periprocedural complications. One patient with ASD II died of recurrent myocardial infarction without evidence of cardioembolic origin. TEE studies showed a residual shunt in 11.2% after 60 days in patients with PFO and a left-to-right shunt in 9.1% of the remaining patients with ASD II. After 180 days only 1 patient with PFO had a right-to-left shunt (3.7%). A residual shunt in the patients with ASD was not observed. CONCLUSIONS: The novel Occlutech devices appear to be safe, feasible and effective for PFO and ASD closure, with a significant reduction of the meshwork and absence of left atrial central pin.

Clinical evaluation of a novel occluder device (Occlutech) for percutaneous transcatheter closure of patent foramen ovale (PFO).

BACKGROUND: We investigated the safety, feasibility and usefulness for closure of PFO with the new nitinol meshwire PFO-occluder device (Occlutech Figulla-single layer occluder) with an unique braiding technology which allows a 50% reduction of meshwork material on the left atrial side in combination with a greater flexibility as compared to the Amplatzer occluder device. METHODS: The retention discs of the new PFO Occlutech Figulla single layer device (23/25 mm) are connected by a 3 mm waist in the centre with only one right atrial side hub. The left atrial disc is a single flat layer covered by an ultrathin polyethylene terephthalate (PET) patch. We investigated the safety, feasibility and usefulness for closure of PFO in a multicenter clinical trial. Indications for closure included cryptogenic stroke with evidence of a patent foramen ovale in transesophageal echocardiography (PFO max. diameter 13 mm according to sizing balloon). The device was implanted in 36 patients (mean age 57, 18-80 years) by means of fluoroscopy and transesophageal echocardiography (TEE) using a 9 French delivery sheath and employing a femoral vein approach. Both acetylsalicylacid 100 mg/d (6 months) and clopidogrel 75 mg/d (3 months) were administered post interventional. A transthoracal (TTE) and transesophageal echocardiography follow-up examination was performed after 1, 2 and 6 months (TTE day 30 and 180; TEE day 60). RESULTS: The device was successfully implanted in 36 pts. In one patient PFO implantations was attempted but not crossed with a guide wire. Perioperativly there were no major in-hospital-adverse events or complications thromboembolism, occluder dislodgement, infection or myocardial infarction. One patient had transient atrial fibrillation 2 h after implantation, which terminated medically after 12 h. TEE studies in the remaining 35 pts (one pt was unwilling to further participate) showed a residual shunt in 8.6% (3/35) after 60 days and a left-to-right shunt in 2.6% (1/35) of pts. After 180 days one pt with severe arteriosclerotic heart disease and A.carotic stenosis revealed a stroke without evidence of cardioembolic origin or devices thrombosis. CONCLUSIONS: The novel Occlutech Figulla PFO N single layer device appears to be safe, feasible and useful for PFO closure despite a 50% reduction of the meshwire, no distal hub and an improved flexibility of the left atrial disc.

First use of a novel plug-and-play percutaneous circulatory assist device for high-risk coronary angioplasty.

OBJECTIVES: Novel circulatory assist devices provide hemodynamic stability in high risk coronary interventions. They ensure sufficient organ perfusion during transfer in case of procedural failure or cardiogenic arrest. We describe the first human use of a novel plug-and-play circulatory assist device for high risk coronary angioplasty. METHODS: An 84 year old lady suffered syncope with complex fracture of the left forearm. Her syncope was related to a subtotal stenosis of the left main coronary artery associated with an acute myocardial infarction. Additional risk factors were previous cardiac surgery, pulmonary disease, diabetes mellitus, and renal insufficiency. Coronary angiography revealed stenosis of both coronary ostia. The emergency assist device LIFEBRIDGE was connected with the patient's circulation by percutaneous cannulation (15F and 17F) of the femoral artery and vein. RESULTS: Stent implantation was performed in both coronary ostia by Judkin's technique. The cannulas were removed two hours after the intervention by local compression. Osteosynthesis of the left radius and ulna was performed five days later under regional anesthesia. The patient was discharged without any complains on day 10. CONCLUSION: This case illustrates the safe and easy use of a novel plug-and-play percutaneous circulatory assist device for high risk interventions. It may be recommended for use in emergency situations.