The imprecision of measuring activated clotting time (ACT) from the guiding catheter during percutaneous coronary interventions.

BACKGROUND: Finding the balance between the reduction in ischemic events and bleeding complications is crucial for the success of percutaneous coronary intervention (PCI). The activated clotting time (ACT) is used routinely worldwide to monitor and titrate anticoagulation therapy with unfractionated heparin (UFH) during the procedure. OBJECTIVES: We aimed to test the accuracy of ACT measurements from the guiding catheter compared to the arterial access sheath. METHODS: Patients undergoing PCI with UFH therapy were prospectively enrolled. Blood samples were drawn from the coronary guide catheter and the arterial access sheath. ACT values were determined in the same ACT machine, and potential interactions with clinical variables were analyzed. RESULTS: The study included 331 patients with post PCI ACT measurements. The mean ACT value of the catheter samples was statistically higher than the arterial access sample [294 ± 77 s Vs. 250 ± 60 s, p < 0.001]. The mean difference between the guiding catheter and the arterial line sheath samples was 43 ± 27 s (P < 0.001). We found that in 101/331 [30 %] patients the ACT from the guiding catheter was above 250 s, while from the access sheath it was below 250 s. Notably, in 40/331 [12 %] the ACT from the guiding catheter was above 200 s, while from the access sheath it was below 200 s. CONCLUSIONS: Large proportion of patient may be considered to have therapeutic ACT if measured from guide catheter during PCI, while the corresponding ACT from arterial sheath is subtherapeutic. This difference may have clinical and safety significance.

Characterization of metabolic alterations in the lean metabolically unhealthy alpha defensin transgenic mice.

Inflammation is consistently linked to dysmetabolism. In transgenic mice (Def+/+) model the neutrophilic peptide, alpha defensin, proved atherogenic. This phenotype occurred despite favorable cholesterol and glucose levels, and lower body weight and blood pressure. In this study, integration of metabolic&behavioral phenotyping system, endocrine, biochemical and mitochondrial assessment, pathological and immunohistochemical tests, and multiple challenge tests was established to explore the metabolic impact of alpha defensin. Compared to the control group, Def+/+ mice exhibited lower total energy expenditure and carbohydrate utilization, and higher fat oxidation. Their ACTH-cortisol and thyroid profiles were intact. Intriguingly, they had low levels of glucagon, with high ammonia, uric acid, triglyceride, and lactate. Mitochondrial evaluations were normal. Overall, defensin-induced hypoglucagonemia is associated with lipolysis, restricted glucose oxidation, and enhanced wasting. Def+/+ mice may be a useful model for studying the category of lean, apparently metabolically healthy, and atherosclerotic phenotype, with insight into a potential inflammatory-metabolic link.

Alleviation of Hepatic Steatosis by Alpha-Defensin Is Associated with Enhanced Lipolysis.

Background and Objectives: The neutrophilic peptide, alpha-defensin, is considered an evolving risk factor intimately linked with lipid mobilization. It was previously linked to augmented liver fibrosis. Here, we assess a potential association between alpha-defensin and fatty liver. Materials and Methods: A cohort of transgenic C57BL/6JDef+/+ male mice that overexpress the human neutrophil-derived alpha-defensin in their polymorphonuclear neutrophils (PMNs) were assessed for liver steatosis and fibrosis development. Wild type (C57BL/6JDef.Wt) and transgenic (C57BL/6JDef+/+) mice were maintained on a standard rodent chow diet for 8.5 months. At the termination of the experiment, systemic metabolic indices and hepatic immunological cell profiling were assessed. Results: The Def+/+ transgenic mice exhibited lower body and liver weights, lower serum fasting glucose and cholesterol, and significantly lower liver fat content. These results were associated with impaired liver lymphocytes count and function (lower CD8, NK cells, and killing marker CD107a). The metabolic cage demonstrated dominant fat utilization with a comparable food intake in the Def+/+ mice. Conclusions: Chronic physiological expression of alpha-defensin induces favorable blood metabolic profile, increased systemic lipolysis, and decreased hepatic fat accumulation. Further studies are needed to characterize the defensin net liver effect.

Facilitated ureteroscopy using DJ stent implantation in ureterolithiasis: A retrospective study.

OBJECTIVE: To investigate the impact of preoperative double J (DJ) stent insertion on outcomes of retrograde semi-rigid ureteroscopy (URS) in patients with upper small and medium sized ureteral stones. METHODS: Between April 2018 and September 2019, we retrospectively reviewed the medical register of Hillel Yaffe tertiary reference Centre (HYMC) for patients who had undergone retrograde semi-rigid URS for urolithiasis. Patients were separated into two groups depending on whether they accepted the DJ stent placement before URS (Group A) or not (Group B). Operating time, stone clearance rate, number of 'rescue' DJ stents, duration of 'rescue' stents, complication rate and requirement for repeat URS were compared between groups. RESULTS: 318 procedures undertaken in 290 patients were included (Group A, 83 procedures in 80 patiants; Group B, 235 procedures in 210 patients). By comparison with the non-stented group, patients in the preoperative DJ stented group had a higher stone clearance rate, lower complication rate, less need for postoperative 'rescue' DJ stent, lower duration of 'rescue' stent and lower re-operative URS requirement, including application of a flexible URS. CONCLUSION: Facilitated semi-rigid URS with upstream DJ stenting for small and medium size ureteral stones has favourable periprocedural outcomes compared with primary URS.

Predictors, Outcomes and Impact of Mechanical Circulatory Support of Patients With Mechanical Complications After Acute Myocardial Infarction.

BACKGROUND: Despite early and currently effective epicardial coronary recanalization, the mortality rate after mechanical complication (MC) remains high, especially in cardiogenic shock. There is an increase in the use of mechanical circulatory support in patients with cardiogenic shock and MC, however, evidence is still scarce and most studies exclude patients with mechanical complications. METHODS: Using the National Inpatient Sample database from 2015 to 2018 to identify patients with AMI, we aimed to determine the predictors and outcomes of patients with MC, subtypes and the use of MCS. RESULTS: We identified 2,427,315 patients with AMI; 2345 (0.1 %) developed MC and of them 1320 (56.3 %) received MCS. Regarding subtypes, 960 (40.9 %) had ventricular septal rupture (VSR), 540 (23.0 %) papillary muscle rupture (PMR), 530 (22.6 %) pseudoaneurysm, and 315 (13.4 %) free wall rupture (FWR). Mortality was 12 times higher (OR: 11.663, CI: 10.582-12.855, p < 0.001) in patients with MC compared to patients without MC (49.7 % vs. 4.6 %, p < 0.001) and all subtypes of MC showed a significant increase in mortality. The use of MCS was associated with decreased mortality in PMR (46.2 % to 34.8 %, p = 0.009) and pseudoaneurysm (64.7 % to 42.1 %, p < 0.001), however, with higher mortality in VSR. CONCLUSIONS: The incidence of MC after an AMI is very low, nonetheless the in-hospital mortality rate remains very high. It tends to occur more in older patients and with fewer comorbidities. The subtype with the highest frequency and highest mortality was VSR. The use of mechanical circulatory support was associated with better survival in PMR and pseudoaneurysm, but not overall survival.

Morphine Use in ST-Elevation Myocardial Infarction With Downstream P2Y12 Receptor Blockers-Insight From Observational Study.

BACKGROUND AND AIMS: Morphine use for patients presenting with NSTE-ACS is associated with excess mortality. However, the role of morphine in STE-ACS is ill characterized. We have recently confirmed direct prothrombotic effect of morphine using murine models. We sought to explore whether morphine use in STE-ACS patients, used to be scheduled for downstream P2Y12 blockers, is negatively associated with procedural and clinical outcomes. METHODS: A single-center, observational retrospective analysis enrolling 130 non-randomized stable patients sustaining STE-ACS as their first manifestation of coronary disease, who presented between December 2010 and June 2013. All were managed by early invasive approach. Of study patients, 55 were treated by morphine, and 75 were not. All were administered downstream P2Y12 blockers according to an already abandoned local policy. Outcomes evaluated included TIMI grade flow, thrombus burden, ST-segment resolution, myocardial function by echocardiography, and cardiovascular death. RESULTS: Morphine administration was associated with a significantly higher incidence of impaired final TIMI grade flow (TIMI < 3, 40% vs 4%, P < .05), lower incidence of ST-segment resolution >70% (40.7% vs 76.5%, P < .05), and a higher incidence of moderate or severe systolic dysfunction (48.1% vs 29.1%, P < .05) compared with morphine naive patients. Interestingly, the overall mortality rate was higher in the morphine-treated group (18% vs 5.3%, P < .05). CONCLUSIONS AND RELEVANCE: Morphine administration combined with the downstream P2Y12 blockers practice signify a group with a higher occurrence of impaired myocardial reperfusion and cardiovascular death despite established on-time primary angioplasty.

Impact of the Admission Pathway on the Gender-Related Mortality of Patients With ST-Elevation Myocardial Infarction.

The mortality of women with ST-elevation myocardial infarction (STEMI) exceeds that of men, supposedly the result of older age and co-morbidities. Patients with STEMI can be transported directly to the catherization lab by the emergency medical service (EMS) or to the emergency department (ED) by the EMS, a regular ambulance, or independently. This raises the question whether gender disparity in the transport of patients with STEMI may affect time to therapy and consequently explain the disparate outcome in men and women with STEMI. We analyzed a large nationwide registry of prospectively-recorded patients with acute coronary syndromes in order to determine if there is a survival gap between men and women with STEMI, and to assess the gender-related effect of admission pathway on time intervals and 5-year mortality. Study population included 2,740 patients with STEMI who underwent primary percutaneous coronary interventions, comprising 464 women (17%, median-70 years) and 2,276 men (83%, median-58 years). The unadjusted 5-year mortality of women was higher compared with men (26.4% vs 15.6%, p = 0.001) but adjustment abrogated this survival difference. Regardless of adjustment, the 5-year mortality of patients with STEMI admitted directly to the catherization lab or to the ED by EMS was similar for men and women but significantly lower in the directly admitted patients (p <0.028). In contrast, admission to the ED by non-EMS was associated with markedly worse survival among women. These results indicate that women suspected of STEMI benefit from transportation by the EMS and should use this pathway exclusively to reach the hospital.

Modern Stents: Where Are We Going?

Coronary artery stenting is the treatment of choice for patients requiring coronary angioplasty. We describe the major advancements with this technology. There have been significant developments in the design of stents and adjunctive medical therapies. Newer-generation drug-eluting stents (DES) have almost negligible restenosis rates and, when combined with proper anti-platelet treatment and optimal deployment, a low risk of stent thrombosis. The introduction of newer-generation DES with thinner stent struts, novel durable or biodegradable polymer coatings, and new antiproliferative agents has further improved the safety profile of early-generation DES. In parallel the effectiveness has been kept, with a significant reduction in the risk of target lesion revascularization compared with the early-generation DES. However, to date, the development of completely bioresorbable vascular scaffolds has failed to achieve further clinical benefits and has been associated with increased thrombosis. Newer-generation DES-including both durable polymer as well as biodegradable polymer-have become the standard of care in all patient and lesion subsets, with excellent long-term results.

Optimal Timing for Coronary Intervention in Patients With Transient ST-Elevation Myocardial Infarction.

STEMI patients admitted urgently to the hospital but experience early complete resolution of both ischemic symptoms and ST-elevations on the electrocardiogram are diagnosed as transient STEMI (TSTEMI). Current evidence indicates that primary intervention is plausible but in certain circumstances intervention can be delayed. We sought to examine whether there is a time limit to such a delay that may affect long-term outcome. Study population included prospectively admitted TSTEMI patients whose demographics, pertinent medical history, and clinical and angiographic features were recorded. Study patients were divided by the median time interval from admission to intervention and their characteristics and long-term survival were compared. Study population comprised 260 consecutive patients (age: 57±10 years, men: 84%) diagnosed as TSTEMI who were included from January 2000 to June 2019, which represent 6% of all STEMI patients. Coronary angiography was performed in 254 patients. The median time interval from admission to angiography was 17 hours (IQR: 7.2 to 38.7 hours). Early (<17 hours from admission) and late (>17 hours from admission) study groups were comparable. One patient died during admission and 41 throughout the long follow-up period of 8.5 ± 5.2 years (median: 8.2 years, IQR: 3.4 to 13.1). Mortality of early-treated TSTEMI patients (11.2%) was significantly lower than of the late-treated patients (21.6%, p <0.04). The Kaplan-Meier curve demonstrated a clear tendency toward improved survival in early-treated TSTEMI patients (p <0.09). In conclusion, the present data suggest that TSTEMI patients should be treated, if not by primary coronary intervention, then at least within 17 hours from admission to achieve better long-term outcome.

Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate.

In patients with acute ischemic stroke, diabetes and hyperglycemia are associated with increased infarct size, more profound neurologic deficits and higher mortality. Notwithstanding extensive clinical and experimental data, treatment of stroke-associated hyperglycemia with insulin is controversial. In addition to hyperglycemia, diabetes and even early prediabetic insulin resistance are associated with increased levels of amino acids, including the neurotoxic glutamate, in the circulation. The pleiotropic metabolic effects of insulin include a reduction in the concentration of amino acids in the circulation. In this article, we show that in diabetic rats exposed to transient middle cerebral artery occlusion, a decrease of plasma glutamate by insulin or glucagon reduces CSF glutamate, improves brain histology, and preserves neurologic function. The neuroprotective effect of insulin and glucagon was similar, notwithstanding their opposite effects on blood glucose. The therapeutic window of both hormones overlapped with the short duration (~30 min) of elevated brain glutamate following brain trauma in rodents. Similar neuroprotective effects were found after administration of the glutamate scavenger oxaloacetate, which does not affect glucose metabolism. These data indicate that insulin and glucagon exert a neuroprotective effect within a very brief therapeutic window that correlates with their capacity to reduce glutamate, rather than by modifying glucose levels.

Urokinase plasminogen activator regulates pulmonary arterial contractility and vascular permeability in mice.

The concentration of urokinase plasminogen activator (uPA) is elevated in pathological settings such as acute lung injury, where pulmonary arterial contractility and permeability are disrupted. uPA limits the accretion of fibrin after injury. Here we investigated whether uPA also regulates pulmonary arterial contractility and permeability. Contractility was measured using isolated pulmonary arterial rings. Pulmonary blood flow was measured in vivo by Doppler and pulmonary vascular permeability, according to the extravasation of Evans blue. Our data show that uPA regulates the in vitro pulmonary arterial contractility induced by phenylephrine in a dose-dependent manner through two receptor-dependent pathways, and regulates vascular contractility and permeability in vivo. Physiological concentrations of uPA (≤1 nM) stimulate the contractility of pulmonary arterial rings induced by phenylephrine through the low-density lipoprotein receptor-related protein receptor. The procontractile effect of uPA is independent of its catalytic activity. At pathophysiological concentrations, uPA (20 nM) inhibits contractility and increases vascular permeability. The inhibition of vascular contractility and increase of vascular permeability is mediated through a two-step process that involves docking to N-methyl-d-aspartate receptor-1 (NMDA-R1) on pulmonary vascular smooth muscle cells, and requires catalytic activity. Peptides that specifically inhibit the docking of uPA to NMDA-R, or the uPA variant with a mutated receptor docking site, abolished both the effects of uPA on vascular contractility and permeability, without affecting its catalytic activity. These data show that uPA, at concentrations found under pathological conditions, reduces pulmonary arterial contractility and increases permeability though the activation of NMDA-R1. The selective inhibition of NMDAR-1 activation by uPA can be accomplished without a loss of fibrinolytic activity.

tPA regulates pulmonary vascular activity through NMDA receptors.

Tissue-type plasminogen activator (tPA) is a potent fibrinolytic enzyme used to treat acute coronary artery obstruction. However, tPA has shown limited utility in other disorders caused by thrombotic vascular occlusion, such as pulmonary embolism. We found that tPA caused dose-dependent effects on the contractility of pulmonary arterial rings that may affect its effectiveness as a thrombolytic agent. At low concentrations (1 nM), tPA stimulated pulmonary vascular contraction in response to phenylephrine, whereas at higher concentrations (20 nM) tPA inhibited pulmonary arterial contractility and promoted pulmonary vascular permeability through an interaction between its "docking site" and N-methyl d-aspartate receptor type 1 (NMDA-R1) expressed by pulmonary arteries. A hexapeptide derived from plasminogen activator inhibitor type 1 that blocked the docking site of tPA, but not its catalytic activity, inhibited its interaction with NMDA-R1, abolished inhibition of pulmonary artery contractility, attenuated vascular permeability, and facilitated fibrinolysis in a murine model of pulmonary embolism. Similar outcomes were seen using a tPA variant that lacks the docking site but retains catalytic activity. These data suggest that it is feasible to attenuate the deleterious extrafibrinolytic effects of tPA and improve its benefit:risk profile in the management of pulmonary embolism.

Neuroprotection by glucagon: role of gluconeogenesis.

OBJECT: The severity of neurological impairment following traumatic brain injury (TBI) is exacerbated by several endogenous processes, including hyperglycemia, hypotension, and the generation of glutamate. However, in addition to controlling hyperglycemia, insulin has pleiotropic effects on tissue metabolism, which include reducing the concentration of the neurotoxic amino acid glutamate, making it unclear whether insulin's beneficial effects are attributable to the establishment of euglycemia per se. In the present study, the authors asked if reducing glutamate via approaches that do not lower glucose levels would improve neurological outcome following TBI. METHODS: Glucagon activates gluconeogenesis by increasing the hepatic uptake of amino acids such as glutamate and facilitating their conversion to glucose. Glucagon was administered as a single intraperitoneal injection before or after closed head injury (CHI). Neurological function, brain histological features, blood glutamate and glucose levels, and CSF glutamate concentrations were measured. RESULTS: A single intraperitoneal injection of glucagon (25 µg) into mice 10 minutes before or after CHI reduced lesion size by about 60% (p < 0.0001) and accelerated neurological recovery. The neuroprotective effect of glucagon was related to gluconeogenesis by decreasing the concentration of the neuroexcitatory amino acid glutamate in the circulation from 207 ± 32.1 µmol/L in untreated mice to 101.11 ± 21.6 µmol/L in treated mice (p < 0.001); a similar effect occurred in the CSF. The neuroprotective effect of glucagon was seen notwithstanding the attendant increase in blood glucose, the final substrate of gluconeogenesis. CONCLUSIONS: Glucagon exerts a marked neuroprotective effect post-TBI by decreasing CNS glutamate. Glucagon was beneficial despite increasing blood glucose. Favorable effects also occurred when glucagon was given prior to TBI, suggesting its involvement in the preconditioning process. Thus, glucagon may be of value in providing neuroprotection when administered after TBI or prior to certain neurosurgical or cardiac interventions in which the incidence of perioperative ischemia is high.

Regulation of airway contractility by plasminogen activators through N-methyl-D-aspartate receptor-1.

Reactive airway disease is mediated by smooth muscle contraction initiated through several agonist-dependent pathways. Activation of type 1 N-methyl-D-aspartate receptors (NMDA-R1s) by plasminogen activators (PAs) has been linked to control of vascular tone, but their effect on airway smooth muscle contractility has not previously been studied to our knowledge. We observed that NMDA-R1s are expressed by human airway smooth muscle cells and constitutively inhibit the contraction of isolated rat tracheal rings in response to acetylcholine (Ach). Both tissue-type PA (tPA) and urokinase-type PA (uPA) bind to NMDA-R1 and reverse this effect, thereby enhancing Ach-induced tracheal contractility. Tracheal contractility initiated by Ach is reduced in rings isolated from tPA(-/-) and uPA(-/-) mice compared with their wild-type counterparts. The procontractile effect of uPA or tPA was mimicked and augmented by the nitric oxide synthase inhibitor, l-NAME. uPA and tPA further enhanced the contractility of rings denuded of epithelium, an effect that was inhibited by the NMDA-R antagonist, MK-801. Binding of PAs to NMDA-R1 and the subsequent activation of the receptor were inhibited by PA inhibitor type 1, by a PA inhibitor type 1-derived hexapeptide that recognizes the tPA and uPA docking domains, as well as by specific mutations within the docking site of tPA. These studies identify involvement of PAs and NMDA-R1 in airway contractility, and define new loci that could lead to the development of novel interventions for reactive airway disease.