His bundle pacing, learning curve, procedure characteristics, safety, and feasibility: Insights from a large international observational study.

BACKGROUND: His-bundle pacing (HBP) provides physiological ventricular activation. Observational studies have demonstrated the techniques' feasibility; however, data have come from a limited number of centers. OBJECTIVES: We set out to explore the contemporary global practice in HBP focusing on the learning curve, procedural characteristics, and outcomes. METHODS: This is a retrospective, multicenter observational study of patients undergoing attempted HBP at seven centers. Pacing indication, fluoroscopy time, HBP thresholds, and lead reintervention and deactivation rates were recorded. Where centers had systematically recorded implant success rates from the outset, these were collated. RESULTS: A total of 529 patients underwent attempted HBP during the study period (2014-19) with a mean follow-up of 217 ± 303 days. Most implants were for bradycardia indications. In the three centers with the systematic collation of all attempts, the overall implant success rate was 81%, which improved to 87% after completion of 40 cases. All seven centers reported data on successful implants. The mean fluoroscopy time was 11.7 ± 12.0 minutes, the His-bundle capture threshold at implant was 1.4 ± 0.9 V at 0.8 ± 0.3 ms, and it was 1.3 ± 1.2 V at 0.9 ± 0.2 ms at last device check. HBP lead reintervention or deactivation (for lead displacement or rise in threshold) occurred in 7.5% of successful implants. There was evidence of a learning curve: fluoroscopy time and HBP capture threshold reduced with greater experience, plateauing after approximately 30-50 cases. CONCLUSION: We found that it is feasible to establish a successful HBP program, using the currently available implantation tools. For physicians who are experienced at pacemaker implantation, the steepest part of the learning curve appears to be over the first 30-50 cases.

Distal Transradial Access for Coronary Angiography and Interventions in Everyday Practice: Data From the TRIANGLE Registry (TwitteR Initiated registry for coronary ANgiography in Germany via distaL radial accEss).

INTRODUCTION: Transradial access (TRA) has become the primary route for coronary angiography (CAG) and percutaneous coronary interventions (PCI). Recently a new puncture site more distally in the area of the anatomical snuffbox has been described. With this multicenter registry, we wish to demonstrate the feasibility and safety of the distal radial access (dRA). METHODS: Between December 2018 and May 2019 all patients with a planned CAG or PCI via dRA in three cardiology centers in Germany were entered into this registry. Procedural data, puncture success, crossover rate and complications were registered. Proximal and distal radial artery patency were examined by ultrasound within 48 h. RESULTS: A total of 327 patients were enrolled (mean age: 69 ± 12 years, 69% male gender, 49% PCI), in 5 cases bilateral distal puncture was performed. Puncture success, defined as completed sheath placement was high (N = 316/332, 95%) and the crossover rate was low (27/332, 8%). The rate of proximal radial artery occlusion after 1-48 h was low (2/332 1%), the rate of occlusion at the distal puncture site was also very low (3/332, 1%). Major complications were not encountered. CONCLUSION: Coronary angiography and interventions via the distal transradial access in the area of the anatomical snuffbox can be performed with a high rate of success and safety. This data suggests a reduced rate of radial artery occlusion compared to previously reported data after cannulation via the standard forearm radial artery puncture site. Randomized studies are needed to further investigate these results. TRIAL REGISTRATION: This study was registered in the German registry for clinical trials: DRKS00017110, retrospectively on 07.May 2019.

Extracellular matrix metalloproteinase inducer regulates matrix metalloproteinase activity in cardiovascular cells: implications in acute myocardial infarction.

BACKGROUND: Matrix metalloproteinases (MMPs) are thought to promote progression of atherosclerosis and cardiovascular complications such as plaque rupture. It has been suggested that, on tumor cells, the extracellular MMP inducer (EMMPRIN) is involved in MMP synthesis by as yet unknown mechanisms. On cardiovascular cells, regulation of EMMPRIN in vivo or any functional relevance for MMP induction in vitro has not yet been studied. Thus, we studied EMMPRIN expression on monocytes in acute myocardial infarction (MI) and its potential relevance for MMP activation. METHODS AND RESULTS: In 20 patients with acute MI, surface expression of EMMPRIN was significantly enhanced on monocytes compared with in 20 patients with chronic stable angina. EMMPRIN upregulation was associated with increased expression of the membrane type 1 MMP (MT1-MMP) on monocytes (flow cytometry) as well as MMP-9 activity (gelatin zymography) in the plasma. At 6 months after successful revascularization, EMMPRIN, MT1-MMP, and MMP-9 had normalized. The secretion of MMP-9 by monocytes was induced by monocyte adhesion to immobilized recombinant EMMPRIN or to EMMPRIN-transfected Chinese hamster ovary cells. Moreover, adherent EMMPRIN-transfected monocytic cells stimulated MMP-2 activity of human vascular smooth muscle cells. Gene silencing of EMMPRIN by small-interfering RNA hindered lipopolysaccharide-induced monocyte secretion of MMP-9, indicating a predominant role of EMMPRIN in MMP-9 induction. CONCLUSIONS: EMMPRIN and MT1-MMP are upregulated on monocytes in acute MI. During cellular interactions, EMMPRIN stimulates MMP-9 in monocytes and MMP-2 in smooth muscle cells, indicating that EMMPRIN may display a key regulatory role for MMP activity in cardiovascular pathologies.

Cytokine profiles and T cell function in acute coronary syndromes.

AIMS: In advanced human atherosclerotic plaques infiltrating T cells congregate at sites of plaque rupture. However, little is known about the systemic activation of circulating T cells in acute coronary syndromes as a prerequisite for recruitment to atherosclerotic lesions. METHODS AND RESULTS: As a measure for specific lymphocyte activation we analyzed IFN-gamma production of T cells after stimulation with a superantigen and expression of CXCR-3 and CCR-3 in patients with acute myocardial infarction (AMI), unstable angina (uAP) or stable angina (sAP). Furthermore, concentrations of the circulating cytokines interleukin (IL)-1, IL-6, IL-1beta, IL-12 p70 and RANTES that modify T cell function were measured. In uAP an increased Th1 and a decreased Th2 response was identified by enhanced interferon-gamma generation of T lymphocytes, increased levels of IL-1beta, IL-12 p70 and RANTES and decreased expression of CCR3. In AMI a systemic inflammatory reaction predominates with enhanced expression of the early activation marker CD69 on T lymphocytes and elevated levels of IL-6 and IL-10 that suppress Th1 activation. CONCLUSION: Interferon-gamma production of activated T cells in acute coronary syndromes may, therefore, be governed by the release of specific pro- and anti-lymphocyte activating cytokines.

The Extracellular Matrix Metalloproteinase Inducer (EMMPRIN, CD147) - a potential novel target in atherothrombosis prevention?

The immunoglobulin superfamily member EMMPRIN (CD147) plays an important role in a number of organ systems, including the cardiovascular system. Here we review the contemporary understanding of EMMPRIN and EMMPRIN-associated sequelae in the course of atherosclerosis. A significant body of data documents the pivotal role of EMMPRIN in the complex processes of atherogenesis, atheroprogression, and acute atherosclerothrombosis, a role that goes beyond that of a mere marker of inflammation.

Extracellular matrix metalloproteinase inducer (CD147) and membrane type 1-matrix metalloproteinase are expressed on tissue macrophages in calcific aortic stenosis and induce transmigration in an artificial valve model.

OBJECTIVE: Matrix metalloproteinases participate in remodeling of extracellular matrix, which is central to the development of aortic stenosis. Synthesis of certain matrix metalloproteinases is induced by the glycoprotein extracellular matrix metalloproteinase inducer. We investigated whether extracellular matrix metalloproteinase inducer and membrane-type 1 matrix metalloproteinase are abundant in calcific aortic valve and their role in the pathogenesis of this condition. METHODS: Sixteen patients who underwent surgery for aortic stenosis (n = 12) or heart transplantation for ischemic cardiomyopathy (n = 4) were reviewed. Expression of extracellular matrix metalloproteinase inducer and membrane-type 1 matrix metalloproteinase proteins was assessed by Western blot (n = 4 per group), immunohistochemistry for aortic stenosis (n = 12) and ischemic cardiomyopathy (n = 2), and in situ zymography (n = 3 per group). Functional relevance was investigated using an artificial valve model. RESULTS: Extracellular matrix metalloproteinase inducer and membrane-type 1 matrix metalloproteinase were abundant in all stenotic valves. Control valves did not stain for either protein. Double immunofluorescence colocalized extracellular matrix metalloproteinase inducer and membrane-type 1 matrix metalloproteinase to macrophages. On Western blotting, both proteins were more abundant in stenotic valves than in control valves. In situ zymography demonstrated greater gelatinolytic activity in stenotic valves than in control valves. Silencing of the extracellular matrix metalloproteinase inducer gene using small interfering RNA reduced migration of monocytes in an artificial valve model. CONCLUSIONS: Extracellular matrix metalloproteinase inducer and membrane-type 1 matrix metalloproteinase were demonstrated on macrophages in stenotic aortic valves, into which extracellular matrix metalloproteinase inducer may promote monocyte immigration. The latter protein may therefore represent a potential target to reduce the development of aortic stenosis.