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Effective progenitor cell recruitment to the ischemic injury zone is a prerequisite for any potential therapeutic effect. Cell uptake determinants in humans with recent myocardial infarction are not defined. We tested the hypothesis that myocardial uptake of autologous CD34+ cells delivered via an intracoronary route after recent myocardial infarction is related to left ventricular (LV) ejection fraction (LVEF) and infarct size.Thirty-one subjects (age, 36-69 years; 28 men) with primary percutaneous coronary intervention-treated anterior ST-segment-elevation myocardial infarction and significant myocardial injury (median peak troponin I, 138 ng/mL [limits, 58-356 ng/mL]) and sustained LVEF depression at 45% were recruited. On day 10 (days 7-12), 4.3×106 (0.7-9.9×106) 99mTc-extametazime-labeled autologous bone marrow CD34+ cells (activity, 77 MBq [45.9-86.7 MBq]) were administered transcoronarily (left anterior descending coronary artery). 99mTc-methoxyisobutyl isonitrile (99mTc-MIBI) single-photon emission computed tomography before cell delivery showed 7 (2-11) (of 17) segments with definitely abnormal/absent perfusion. Late gadolinium-enhanced infarct core mass was 21.7 g (4.4-45.9 g), and infarct border zone mass was 29.8 g (3.9-60.2 g) (full-width at half-maximum, signal intensity thresholding algorithm). One hour after administration, 5.2% (1.7%-9.9%) of labeled cell activity localized in the myocardium (whole-body planar γ scan). Image fusion of labeled cell single-photon emission computed tomography with LV perfusion single-photon emission computed tomography or with cardiac magnetic resonance infarct imaging indicated cell uptake in the peri-infarct zone. Myocardial uptake of labeled cells activity correlated in particular with late gadolinium-enhanced infarct border zone mass (r=0.84, P<0.0001); it also correlated with peak TnI (r=0.76, P<0.001), severely-abnormal/absent perfusion segment number (r=0.45, P=0.008), and late gadolinium-enhanced infarct core (r=0.58, P=0.0003) but not with echocardiography LVEF (r=-0.07, P=0.68) or gated single-photon emission computed tomography LVEF (r=-0.28, P=0.16. The correlation with cardiac magnetic resonance imaging-LVEF was weak (r=-0.38; P=0.04).This largest human study with labeled bone marrow CD34+ cell transcoronary transplantation after recent ST-segment-elevation myocardial infarction found that myocardial cell uptake is determined by infarct size rather than LVEF and occurs preferentially in the peri-infarct zone. [ABSTRACT FROM AUTHOR]

Background: For transcoronary progenitor cells' administration, injections under flow arrest (over-the-wire balloon technique, OTW) are used universally despite lack of evidence for being required for cell delivery or being effective in stimulating myocardial engraftment. Flow-mediated endothelial rolling is mandatory for subsequent cell adhesion and extravasation.Methods: To optimize cell directing toward the coronary endothelium under maintained flow, the authors developed a cell-delivery side-holed perfusion catheter (PC). Thirty-four patients (36-69 years, 30 men) with primary stent-assisted angioplasty-treated anterior MI (peak TnI 151 [53-356]ng/dL, mean[range]) were randomly assigned to OTW or PC autologous ⁹⁹Tc-extametazime-labeled bone marrow CD34(+) cells (4.34 [0.92-7.54] × 10⁶) administration at 6-14 days after pPCI (LVEF 37.1 [24-44]%). Myocardial perfusion (⁹⁹(m)Tc-MIBI) and labeled cells' activity were evaluated (SPECT) at, respectively, 36-48 h prior to and 60 min after delivery.Results: In contrast to OTW coronary occlusions, no intolerance or ventricular arrhythmia occurred with PC cells' administration (P < .001). One hour after delivery, 4.86 [1.7-7.6]% and 5.05 [2.2-9.9]% activity was detected in the myocardium (OTW and PC, respectively, P = .84). Labeled cell activity was clearly limited to the (viable) peri-infarct zone in 88% patients, indicating that the infarct core zone may be largely inaccessible to transcoronary-administered cells.Conclusions: Irrespective of the transcoronary delivery method, only ≈ 5% of native (i.e., non-engineered) CD34(+) cells spontaneously home to the injured myocardium, and cell retention occurs preferentially in the viable peri-infarct zone. Although the efficacy of cell delivery is not increased with the perfusion method, by avoiding provoking ischemic episodes PC offers a rational alternative to the OTW delivery. [ABSTRACT FROM AUTHOR]

Background: For transcoronary progenitor cells' administration, injections under flow arrest (over-the-wire balloon technique, OTW) are used universally despite lack of evidence for being required for cell delivery or being effective in stimulating myocardial engraftment. Flow-mediated endothelial rolling is mandatory for subsequent cell adhesion and extravasation. Methods: To optimize cell directing toward the coronary endothelium under maintained flow, the authors developed a cell-delivery side-holed perfusion catheter (PC). Thirty-four patients (36-69 years, 30 men) with primary stent-assisted angioplasty-treated anterior MI (peak TnI 151 [53-356]ng/dL, mean[range]) were randomly assigned to OTW or PC autologous Tc-extametazime-labeled bone marrow CD34 cells (4.34 [0.92-7.54] × 10) administration at 6-14 days after pPCI (LVEF 37.1 [24-44]%). Myocardial perfusion (Tc-MIBI) and labeled cells' activity were evaluated (SPECT) at, respectively, 36-48 h prior to and 60 min after delivery. Results: In contrast to OTW coronary occlusions, no intolerance or ventricular arrhythmia occurred with PC cells' administration ( P < .001). One hour after delivery, 4.86 [1.7-7.6]% and 5.05 [2.2-9.9]% activity was detected in the myocardium (OTW and PC, respectively, P = .84). Labeled cell activity was clearly limited to the (viable) peri-infarct zone in 88% patients, indicating that the infarct core zone may be largely inaccessible to transcoronary-administered cells. Conclusions: Irrespective of the transcoronary delivery method, only ≈5% of native (i.e., non-engineered) CD34 cells spontaneously home to the injured myocardium, and cell retention occurs preferentially in the viable peri-infarct zone. Although the efficacy of cell delivery is not increased with the perfusion method, by avoiding provoking ischemic episodes PC offers a rational alternative to the OTW delivery. [ABSTRACT FROM AUTHOR]

We have recently shown that exogenous nitric oxide (NO) elicits a positive chronotropic response by stimulating the hyperpolarization activated current, If. Objective: To examine whether l-arginine (l-Arg) can mimic the chronotropic effect of NO by enhancing its endogenous production. Methods: In spontaneously beating guinea pig atria we evaluated the heart rate (HR) response to increasing concentrations of l-Arg (1 μmol/l to 10 mmol/l), and compared it with that for d-Arg or l-lysine (l-Lys) (all in free base (FB) or hydrochloride (HCl) formulation). Results: l-ArgFB >100 μmol/l caused a reversible dose-dependent increase in HR (peak effect +64±7 bpm at 10 mmol/l, P<0.05, n=8). However, a similar HR response occurred with d-ArgFB (n=7) or l-LysFB (n=6). All FB formulations increased the perfusate pH (peak [pH]o=8.61±0.03). Although alkalinization can stimulate NO release from the endothelium, this is unlikely to have contributed to HR changes in our preparation, since neither NG-methyl-l-arginine, (100–500 μmol/l, which per se reduced HR by 8±1%, P<0.05, n=9) nor NO scavenging (fresh 5% red blood cells, n=9) caused a rightward shift of the concentration–response curve to l-ArgFB. Furthermore, as opposed to FB formulations, L-ArgHCl, d-ArgHCl or l-LysHCl >1 mmol/l significantly decreased HR and [pH]o (n=17). The chronotropic effects of l-ArgFB or l-ArgHCl were reproduced by changing [pH]o with NaOH (n=8) or HCl (n=7), whereas the HR increase with l-ArgFB was prevented by clamping [pH]o at 7.42±0.07 (n=10). Conclusions: In vitro, l-Arg can markedly affect HR through a pH-mediated, NO-independent mechanism. Our data show that the opposing changes in [pH]o induced by different formulations of l-Arg can importantly confound the assessment of the biological effects of this amino acid. [ABSTRACT FROM PUBLISHER]

The article focuses on the use of single-photon emission computed tomography (SPECT) to visualize the early myocardial engraftment of autologous CD34 cells delivered through cell-delivery perfusion catheter. It notes that the catheter was designed to direct the cells towards endothelium while maintaining the coronary flow. The result showed that any physiological migration process requires cells' rolling in contact with arterial endothelium in the presence of coronary flow.

Today, endovascular treatment (EVT) is the therapy of choice for strokes due to acute large vessel occlusion, irrespective of prior thrombolysis. This necessitates fast, coordinated multi-specialty collaboration. Currently, in most countries, the number of physicians and centres with expertise in EVT is limited. Thus, only a small proportion of eligible patients receive this potentially life-saving therapy, often after significant delays. Hence, there is an unmet need to train a sufficient number of physicians and centres in acute stroke intervention in order to allow widespread and timely access to EVT. To provide multi-specialty training guidelines for competency, accreditation and certification of centres and physicians in EVT for acute large vessel occlusion strokes. The World Federation for Interventional Stroke Treatment (WIST) consists of experts in the field of endovascular stroke treatment. This interdisciplinary working group developed competency – rather than time-based – guidelines for operator training, taking into consideration trainees' previous skillsets and experience. Existing training concepts from mostly single specialty organizations were analysed and incorporated. The WIST establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in EVT. WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. WIST multispecialty guidelines outline competency and quality standards for physicians and centres to perform safe and effective EVT. The role of quality control and quality assurance is highlighted. The World Federation for Interventional Stroke Treatment (WIST) establishes an individualized approach to acquiring clinical knowledge and procedural skills to meet the competency requirements for certification of interventionalists of various disciplines and stroke centres in endovascular treatment (EVT). WIST guidelines encourage acquisition of skills using innovative training methods such as structured supervised high-fidelity simulation and procedural performance on human perfused cadaveric models. WIST multispecialty guidelines outline competency and quality standards for physicians and centers to perform safe and effective EVT. The role of quality control and quality assurance is highlighted. The WIST 2023 Guidelines are published simultaneously in Europe (Adv Interv Cardiol 2023). • Widespread and timely interventional stroke treatment requires multiple specialties. • Training requirements for interventional stroke treatment are outlined. • Special emphasis rests on simulator and human cadaver training. • The pathway for an operator to reach WIST certification is specified. [ABSTRACT FROM AUTHOR]

Large amounts of clot-bound lipoproteins were reported in proteomic analysis of plasma clot but their impact on fibrin clot properties is unknown. We investigated a contribution of lipid profile and apolipoproteins (apo) to the prothrombotic plasma fibrin clot phenotype in patients with aortic stenosis (AS). In 138 patients with isolated severe AS, we determined serum apoA-I, A-II, B, C-II, C-III, E, oxidized low-density lipoprotein (OxLDL) and lipoprotein(a) concentrations. Plasma fibrin clot permeability (Ks), maximal absorbance (MaxAbs CLT2018 and MaxAbs Lys50), and fibrinolytic capacity were studied using 3 plasma-based lysis assays (CLT2018, CLT, and Lys50), and compared with well-matched patients without AS (control group). After adjustment for confounding factors, including statin use, only low-density lipoprotein cholesterol (LDL-C) and apoB levels were inversely associated with Ks. Triglycerides, apoC-II, and C-III were associated with MaxAbs CLT2018 and MaxAbs Lys50 , explaining 56–64% of their variability. CLT2018 and CLT showed associations with total cholesterol, LDL-C, triglycerides, and OxLDL as well as with apoB, C-II, C-III, and E. ApoA-I, C-II, and C-III but not serum lipids were associated with Lys50. Only CLT2018 was associated with lipoprotein(a). ApoC-III, B, A-I, and E along with estimated glomerular filtration rate and OxLDL predicted hypofibrinolysis in multiple regression analysis. AS patients had higher lipoprotein(a) (+34.9%) and apoA-I (+25.9%) levels and less compact fibrin clots (−13.3% lower MaxAbs CLT2018 , -53.2% lower MaxAbs Lys50 , and +28.3% higher Ks) displaying higher susceptibility to lysis (−17.9% lower Lys50) in comparison with control group. Apolipoproteins and OxLDL contribute to prothrombotic fibrin clot phenotype in severe AS. Moreover, apolipoproteins better than serum lipids predicted hypofibrinolysis, which provides additional argument for a role of elevated lipoproteins in the prothrombotic state. [Display omitted] • Apolipoproteins contribute to prothrombotic fibrin clot phenotype in severe aortic stenosis (AS). • Apolipoproteins could predict hypofibrinolysis better than serum lipids. • Statins have beneficial effects on fibrin clot structure and function in severe AS. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury remains a major clinical problem in patients with ST-elevation myocardial infarction (STEMI), leading to myocardial damage despite early reperfusion by primary percutaneous coronary intervention (PPCI). There are no effective therapies to limit ischemia-reperfusion injury, which is caused by multiple pathways activated by rapid tissue reoxygenation and the generation of reactive oxygen species (ROS). FDY-5301 contains sodium iodide, a ubiquitous inorganic halide and elemental reducing agent that can act as a catalytic anti-peroxidant. We tested the feasibility, safety and potential utility of FDY-5301 as a treatment to limit ischemia-reperfusion injury, in patients with first-time STEMI undergoing emergency PPCI. STEMI patients (n = 120, median 62 years) presenting within 12 h of chest pain onset were randomized at 20 PPCI centers, in a double blind Phase 2 clinical trial, to receive FDY-5301 (0.5, 1.0 or 2.0 mg/kg) or placebo prior to reperfusion, to evaluate the feasibility endpoints. Participants underwent continuous ECG monitoring for 14 days after PPCI to address pre-specified cardiac arrhythmia safety end points and cardiac magnetic resonance imaging (MRI) at 72 h and at 3 months to assess exploratory efficacy end points. Intravenous FDY-5301 was delivered before re-opening of the infarct-related artery in 97% participants and increased plasma iodide levels ~1000-fold within 2 min. There was no significant increase in the primary safety end point of incidence of cardiac arrhythmias of concern. MRI at 3 months revealed median final infarct sizes in placebo vs. 2.0 mg/kg FDY-5301-treated patients of 14.9% vs. 8.5%, and LV ejection fractions of 53.9% vs. 63.2%, respectively, although the study was not powered to detect statistical significance. In patients receiving FDY-5301, there was a significant reduction in the levels of MPO, MMP2 and NTproBNP after PPCI, but no reduction with placebo. Intravenous FDY-5301, delivered immediately prior to PPCI in acute STEMI, is feasible, safe, and shows potential efficacy. A larger trial is justified to test the effects of FDY-5301 on acute ischemia-reperfusion injury and clinical outcomes. Clinical Trial Registration: CT.gov NCT03470441 ; EudraCT 2017-000047-41 • This phase 2a trial tested intravenous FDY-5301, containing sodium iodide, to prevent IR injury in heart attack patients • FDY-5301 was successfully given within 2 min, before opening the blocked coronary artery • FDY-5301 was safe, with no significant adverse events • FDY-5301 showed promising trends to reduce heart attack damage • This result justify a Phase 3 clinical outcomes trial of FDY-5301 in acute heart attack patients [ABSTRACT FROM AUTHOR]