Abstract Aims To assess the clinical characteristics and compare in–hospital outcomes of elderly and non–elderly patients receiving cangrelor in the peri–percutaneous coronary intervention (PCI) phase. Methods Consecutive patients treated with cangrelor in 7 Italian institutions were retrospectively enrolled in the ICARUS (“Intravenous CAngrelor in high–bleeding Risk patients Undergoing percutaneouS coronary intervention”, NCT05505591) registry. Elderly patients were defined if age was ≥75 years at the time of PCI. The primary endpoint was net adverse clinical events (NACE), defined as a composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis and Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding, at 48 hours. Secondary endpoints were assessed at 48 hours and throughout the hospital stay. Independent predictors of the primary endpoint were also assessed. Results Out of 551 patients undergoing PCI with cangrelor between January 2019 and August 2022, 174 (32%) were elderly. Mean age was 81±5 vs. 61±8 years in elderly vs. non–elderly patients (p<0.001). Female sex (32% vs. 21%, p=0.006), atrial fibrillation (20% vs. 5%, p<0.001), chronic kidney disease (30% vs. 6%, p<0.001) and heart failure (14% vs. 8%, p=0.041) were more frequent in the elderly group, whereas presentation with acute coronary syndrome (ACS) was less frequent (69% vs. 83%, p=0.001). Elderly patients received shorter cangrelor infusion (122±25 vs. 134±43 minutes, p=0.001) and were more frequently administered with clopidogrel after PCI (50% vs. 19%, p<0.001). At 48 hours, elderly patients had higher rates of NACE (13% vs. 6%, p=0.006) and BARC 2, 3 or 5 bleeding (11% vs. 5%, p=0.013), whereas the rates of other 48–hour and in–hospital clinical endpoints did not differ. At multivariable analysis, age ≥75 years (odds ratio [OR] 1.07, 95% CI 1.02–1.12, p=0.004), major anemia (OR 1.10, 95% CI 1.005–1.22, p=0.038), ACS at presentation (OR 1.08, 95% CI 1.03–1.14), femoral access (OR 1.13, 95% CI 1.06–1.22) and cardiogenic shock (OR 1.35, 95% CI 1.21–1.50) independently predicted the occurrence of 48–hour NACE. Conclusions Advanced age is a distinctive risk feature among patients receiving intravenous cangrelor in the peri–PCI phase. Elderly patients had higher rates of adverse events at 48 hours, with advanced age (≥75 years) being an independent predictor of NACE.

Abstract Aims To compare the clinical characteristics and in–hospital outcomes of patients undergoing complex vs. non–complex percutaneous coronary intervention (PCI) with peri–procedural use of cangrelor. Methods Consecutive patients treated with cangrelor in 6 Italian institutions were retrospectively enrolled in the ICARUS (“Intravenous CAngrelor in high–bleeding Risk patients Undergoing percutaneouS coronary intervention”, NCT05505591) registry. Complex PCI was defined as any of the following: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion. The primary endpoint was net adverse clinical events (NACE), defined as a composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis and Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding, at 48 hours. Secondary endpoints were assessed at 48 hours and throughout the hospital stay. Results Among 551 patients enrolled in the ICARUS registry and undergoing PCI between January 2019 and August 2022, a total of 534 (97%) patients had complete information on PCI complexity, of whom 173 (32%) underwent complex PCI and 361 (68%) underwent non–complex PCI. In general, patients with complex PCI had similar clinical features compared with non–complex PCI patients, including comparable prevalence of high bleeding risk (HBR) status according to the ARC–HBR definition (35% vs. 30%, p=0.253), but complex PCI patients presented more often with cardiogenic shock (9% vs. 2%, p<0.001). PCI with ≥3 stents implanted was the most frequent criterion of procedural complexity (62%). The incidence of the primary endpoint of 48–hour NACE (10% vs. 7%, p=0.264) and other clinical endpoints occurring at 48 hours or during hospitalization did not differ between complex and non–complex PCI patients. Conclusions Among patients receiving peri–procedural cangrelor, about 30% of cases underwent complex interventions. Notwithstanding higher procedural complexity, short–term clinical outcomes were similar between complex and non–complex PCI patients.

Spontaneous coronary artery dissection (SCAD) is recently emerging as an increasingly frequent cause of myocardial infarction and among the main triggering factors we found hypertension, pregnancy, fibromuscular dysplasia and connective tissue diseases (e.g. Marfan syndrome). Recent studies also suggest that even bicuspid aortic valve may be a predisposing condition for the development of spontaneous coronary artery dissection. We report the case of a 45–year–old Caucasian man with no cardiovascular risk factors; his clinical history begins in August 2019, when he was hospitalized for acute coronary syndrome (NSTEMI). Echocardiography showed preserved left ventricular ejection fraction, bicuspid aortic valve (fusion of right and left cusps) with mild to moderate regurgitation without stenosis and mild dilatation of the aortic bulb (38 mm). The coronary angiography showed no significant stenoses and an anomalous origin of the right coronary artery from the common trunk. The patient was discharged two days later with a diagnosis of MINOCA and an indication to perform a coronary CT scan, which confirmed the anomalous origin of the right coronary artery with a retro–aortic course, and a cardiac MRI, which showed myocardial edema of the infero–lateral wall, mainly with sub–endocardial distribution and LGE in the same sites, compatible with ischemic damage. In September 2022 there was a new hospitalization for inferior–posterior–lateral STEMI with coronarographic finding of a large marginal branch collateral stenosis, with recovery of distal caliber. The angiographic pattern was consistent with type II SCAD (no intracoronary imaging has been performed because of vascular tortuosity and lesion distality). A retrospective comparative analysis of the 2019 angiography allowed to find a distal occlusion of the same branch, now healed, also compatible with SCAD. The patient was discharged on single antiplatelet therapy after one week of DAPT with acetylsalicylic acid and clopidogrel and indication to perform a genetic test for connective tissue diseases. The case described prompts the cardiologists to suspect an uncommon etiology (connective tissue disease, bicuspid aortic valve) in case of SCAD detection, especially if associated with anomalous origin of the coronary arteries.

Abstract Aims To investigate the prevalence of high bleeding risk (HBR) criteria and compare clinical outcomes between HBR and non–HBR patients receiving cangrelor in the peri–percutaneous coronary intervention (PCI) phase. Methods Consecutive patients treated with cangrelor in 7 Italian institutions were retrospectively enrolled in the ICARUS (“Intravenous CAngrelor in high–bleeding Risk patients Undergoing percutaneouS coronary intervention”, NCT05505591) registry. HBR status was assessed according to the Academic Research Consortium (ARC–HBR) definition. The primary endpoint was net adverse clinical events (NACE), defined as a composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis and Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding, at 48 hours. Secondary endpoints were assessed at 48 hours and throughout the hospital stay. Results We enrolled 551 patients undergoing PCI with cangrelor between January 2019 and August 2022. HBR definition was met in 33% of cases. HBR patients were older (76±10 vs. 63±10 years, p<0.001), more frequently affected by peripheral arterial disease (16% vs. 8%, p=0.010), atrial fibrillation (24% vs. 2%, p<0.001), chronic kidney disease (35% vs. 3%, p<0.001), active cancer (7% vs. 0%, p<0.001) and heart failure (17% vs. 7%, p<0.001). At 48 hours, HBR patients had a significantly higher rate of NACE (13% vs. 6%, p=0.004), and BARC 2, 3 or 5 bleeding (12% vs. 4%, p=0.001). In the HBR group, the frequency of the primary endpoint increased proportionally to the HBR score. There was no significant difference with respect to other 48–hour and in–hospital endpoints. Conclusions Among consecutive patients treated with cangrelor in the peri–PCI phase, about 30% fulfilled the ARC–HBR definition. In the HBR subpopulation, the incidence of 48–hour adverse events was higher than in the non–HBR subgroup, primarily driven by a higher rate of clinically relevant and major bleeding.

Abstract Background Little is known about intraprocedural and mid–term results of intravascular lithotripsy (IVL) use in patients with acute MI. Methods In Our retrospective analysis, data from 21 Centers in Italy and Spain between January 2020 and November 2021 were collected. Patients were allocated to the AMI–group when IVL was performed during an acute MI. Primary safety endpoint was defined as freedom from major adverse cardiac events (MACE: cardiac death, myocardial infarction (MI), target vessel revascularization (TLR) or stent thrombosis (ST)) within 30 days of the index procedure, and primary effectiveness endpoint was procedural success (defined as stent delivery with a residual stenosis <20% and without intraprocedural MACE). The mid–term endpoint was 6–months MACE. Results A total of 468 patients were retrospectively enrolled. The primary safety endpoint was achieved in 98.8% of patients in the AMI–group and in 98.5% in the non–AMI group (p=NS). We showed a lower incidence of the primary effectiveness endpoint in the AMI–group (89.8%) vs Non AMI–group (94.8%) (p=0.048). The secondary endpoint of 6–months MACE was similar between groups (6.7% vs 4.9% respectively for AMI group and Non AMI–group), but death for cardiac causes occurred more frequently in the AMI–group (4.3% vs 0%, p=0.01). Conclusions Intravascular lithotripsy demonstrated to be a safe tool for the treatment of calcified coronary lesions during Acute Myocardial infarction, even if we showed some concern for lower procedural success.

BACKGROUND The benefit of complete revascularization in older patients (≥75 years of age) with myocardial infarction and multivessel disease remains unclear. METHODS In this multicenter, randomized trial, we assigned older patients with myocardial infarction and multivessel disease who were undergoing percutaneous coronary intervention (PCI) of the culprit lesion to receive either physiology-guided complete revascularization of nonculprit lesions or to receive no further revascularization. Functionally significant nonculprit lesions were identified either by pressure wire or angiography. The primary outcome was a composite of death, myocardial infarction, stroke, or any revascularization at 1 year. The key secondary outcome was a composite of cardiovascular death or myocardial infarction. Safety was assessed as a composite of contrast-associated acute kidney injury, stroke, or bleeding. RESULTS A total of 1445 patients underwent randomization (720 to receive complete revascularization and 725 to receive culprit-only revascularization). The median age of the patients was 80 years (interquartile range, 77 to 84); 528 patients (36.5%) were women, and 509 (35.2%) were admitted for ST-segment elevation myocardial infarction. A primary-outcome event occurred in 113 patients (15.7%) in the complete-revascularization group and in 152 patients (21.0%) in the culprit-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.57 to 0.93; P = 0.01). Cardiovascular death or myocardial infarction occurred in 64 patients (8.9%) in the complete-revascularization group and in 98 patients (13.5%) in the culprit-only group (hazard ratio, 0.64; 95% CI, 0.47 to 0.88). The safety outcome did not appear to differ between the groups (22.5% vs. 20.4%; P = 0.37). CONCLUSIONS Among patients who were 75 years of age or older with myocardial infarction and multivessel disease, those who underwent physiology-guided complete revascularization had a lower risk of a composite of death, myocardial infarction, stroke, or ischemia-driven revascularization at 1 year than those who received culprit-lesion-only PCI. (Funded by Consorzio Futuro in Ricerca and others; FIRE ClinicalTrials.gov number, NCT03772743.).

Plastic is one of the main sources of marine and terrestrial pollution. This material can fragment into micro- (<-5 mm) and nanoplastics (NPs) (<100 nm) following degradation. Animals are exposed to these particles by ingesting contaminated food, respiration or filtration, and transdermally. In organisms, NPs can cross biological membranes, and cause oxidative stress, cell damage, apoptosis, and endocrine interference. We previously demonstrated that polystyrene - NPs interfered with ovarian cell functions. Since reproduction involves a high energy expenditure and a crucial role is played by adipose tissue, the aim of the present study was to evaluate the effects of NPs on primary adipose stromal cells (ASCs) isolated from swine adipose tissues. In particular, the effects on cell viability, proliferation, metabolic activity, inflammatory process mediators and oxidative stress markers were assessed. The obtained results did not reveal a significant variation in cell proliferation, metabolic activity was increased (P < 0.01) but only at the lowest concentration, while viability showed a significant decrease after prolonged exposure to NPs (P < 0.01). TNF-α was increased (P < 0.05), while PAI-1 was inhibited (P < 0.001). Redox status was significantly modified; in particular, the production of O2-, H2O2 and NO was stimulated (P < 0.05), the non-enzymatic antioxidant power was reduced (P < 0.05) while catalase activity was significantly (P < 0.01) increased.

Soil, water, and air pollution by plastic represents an issue of great concern since the particles produced by degradation of plastic materials can be ingested by animals and humans, with still uncertain health consequences. As a contribution on this crucial subject, the present work reports an investigation on the in vitro effects of different concentrations of polystyrene nanoplastics (5, 25, and 75 µg/mL) on swine granulosa cells, a model of endocrine reproductive cells. In particular, cell growth (BrDU incorporation and ATP production), steroidogenesis (17-β estradiol and progesterone secretion) and redox status (superoxide and nitric oxide production, enzymatic and non-enzymatic scavenging activity) were studied. Nanoplastics, at the highest concentration, stimulated cell proliferation (P < 0.05), while cell viability resulted unaffected. Steroidogenesis was disrupted (P < 0.05). Both enzymatic and non-enzymatic scavenging activity were increased after exposure at the highest nanoplastic dose (P < 0.05, P < 0.001). Nitric oxide secretion was increased by 25 and 75 µg/mL (P < 0.05) while superoxide generation was stimulated (P < 0.001) only by the highest concentration tested. Taken together, main features of cultured swine granulosa cells resulted affected by exposure to nanoplastics. These results raise concerns since environment nanoplastic contamination can represents a serious threat to animal and human health.

We evaluated the efficacy of oral sildenafil citrate in dogs with congenital idiopathic megaoesophagus (CIM). Twenty-one puppies were randomly assigned to two groups (treatment and control). The dogs were given sildenafil oral suspension 1 mg/kg every 12 hours for 14 days or placebo in a masked fashion. Clinical signs (frequency of regurgitation and weight gain) and oesophagrams (relative oesophageal diameter, ROD) were evaluated in order to assess the efficacy of drug treatment, by examiners who were unaware of the study protocol. In addition, a set of in vitro experiments on isolated samples of canine lower oesophageal sphincter (LOS) was performed, and the effects of increasing concentrations of sildenafil on basal tone and electrically-stimulated motility were assessed. Sildenafil administration significantly reduced the number of regurgitation episodes (0.88±1.40 v 2.65±1.56, P<0.0001) and significantly increased weight gain in the treated dogs compared to controls (79.76±28.30 per cent v 53.40±19.30 per cent, P=0.034). ROD values, at the end of the treatment period, were significantly decreased in the sildenafil group, compared to pre-treatment values (0.97±0.19 v 0.24±0.14, P<0.0001), in contrast to control subjects (0.98±0.17 v 1.10±0.25, P=0.480). In accordance with the in vivo findings, sildenafil dose-dependently reduced basal tone and increased electrically-induced relaxation of dog LOS samples. These results suggest that sildenafil citrate helps ameliorate clinical and radiographic signs in dogs with CIM by reducing LOS tone, and could represent a novel therapeutic tool for the treatment of this disease.

We investigated the effects of different selective α2 -adrenergic receptor (AR) agonists (detomidine, medetomidine, xylazine, and brimonidine) on the contractions of horse-isolated bronchi induced by electrical field stimulation (EFS) and by carbachol. No effects were observed on the contraction induced by carbachol, while α2 -AR agonists reduced EFS-evoked contractions in a concentration-related fashion. The rank order of potency (pD2 ) was brimonidine (7.40 ± 0.20) >medetomidine (7.09 ± 0.24) >detomidine (6.13 ± 0.55) >xylazine (4.59 ± 0.16). The maximal effects (Emax ) were -56.3% ± 6.3%, -40.4% ± 6.9%, -48.6% ± 9.9%, and -72.7% ± 12.7% for brimonidine, medetomidine, detomidine, and xylazine, respectively. Adrenergic block by guanethidine enhanced the potency (8.10 ± 0.05, 7.30 ± 0.15, 6.83 ± 0.41, and 5.40 ± 0.22) and the efficacy (-95.2% ± 0.7%, -45.2% ± 11.7%, -58.5% ± 9.8%, and -97.9% ± 0.6%) of brimonidine, medetomidine, detomidine, and xylazine, respectively. Selective α2 -AR antagonist, atipamezole, competitively antagonized the inhibition of EFS-evoked contractions induced by all agonists except xylazine. These results suggest the existence of presynaptic α2 -ARs on cholinergic neurons, negatively regulating the release of acetylcholine in horse bronchial muscle, and that α2 -AR agonists may be beneficial against vagally mediated bronchoconstriction.

Sera from Dirofilaria immitis-experimentally infected dogs treated with a combination of ivermectin/doxycycline were analysed for doxycycline levels by HPLC and anti-Wolbachia Surface Protein (rWSP) antibodies by ELISA and compared with sera from dogs treated with doxycycline alone. Results show that doxycycline levels were not statistically different between the two groups. Circulating anti-WSP antibody titres were markedly lower in both treatment groups when compared to control D. immitis infected dogs, indicating that doxycycline is able to reduce Wolbachia and prevent the immune response against the bacteria. The combination treatment protocol has been shown to be highly adulticidal and further studies are needed to better understand the interaction between doxycycline and ivermectin in D. immitis infected dogs.

Introduction - Caffeine (1,3,7 trimethylxanthine) is a natural alkaloid and one of the most widely employed psychoactive substances which induces several important stimulatory effects on central nervous system such as enhanced alertness, decreased fatigue and stimulation of respiratory center. Caffeine, which is currently employed for the treatment of neonatal hypoxia in humans, could also be beneficial against perinatal asphyxia in piglets, that is responsible of high mortality rates and poor weight gain.Aim - The aim of this study was a preliminary assessment of caffeine pharmacokinetic parameters in sows. Moreover, this study could provide information on caffeine pharmacokinetics in pigs which could be of great help for the possible therapeutic use of this drug, as in vivo information regarding ADME (Absorption Distribution Metabolism Excretion) behaviour of the methylxanthine in this species are thus far lacking.Materials and methods - In our experimental design, a single dose of 25 mg/kg of caffeine was given orally to six healthy sows, mixed with 200 g of lactation feed given before morning meal. Blood samples were collected at specific times and caffeine levels in plasma were measured by means of HPLC method. The dose was chosen according to a previously published study. The method was intra-laboratory validated according to EMA guidelines (2012).Results and discussion - No adverse effects were observed in the animals after caffeine administration. Caffeine concentration reached a peak (C-max = 20.02 +/- 1.51 mu g/mL) at 9.51 +/- 1.17 h and declined displaying a bi-phasic behaviour. Our pharmacokinetic data were suggestive of a slower elimination compared to humans, monkeys, rabbits and rodents, while they were similar to those observed in other species like sheep, cattle and equines. An interesting clinical implication of our study could be suggested by the concentration-time curve of orally administered caffeine, showing plasma levels at 24 h after treatment of 13.77 +/- 0.97 mu g/mL. Such blood levels of caffeine are similar to those detected in human neonates treated for perinatal hypoxia. Since caffeine is known to freely cross the placenta and, therefore, to reach the same levels in fetal as in maternal blood, our data seem to support a previous study, in which oral caffeine administration to sows the day before parturition was able to improve the vitality of newborn piglets.Conclusions - This study provides first data about pharmacokinetics of caffeine in pigs and suggests a possible clinical utility in swine. However, further experiments with diverse doses and routes of administration of caffeine, and in farrowing sows, are needed to enlighten its pharmacokinetic profile.

We investigated the effects of nonselective muscarinic antagonist (atropine) and of selective muscarinic subtype 1 (M1), 2 (M2), 3 (M3) antagonists (VU0255035, methoctramine, pFHHSiD, respectively) on the contractions evoked by electrical field stimulation (EFS) or by exogenous ACh in isolated horse bronchial muscle. Atropine completely inhibited neurogenic contractions in a concentration-dependent fashion, whereas selective muscarinic antagonists induced relevant modifications only at the highest concentration tested. Experiments with selective muscarinic antagonists in combination showed that only the simultaneous blockade of M1 /M3 or M2 /M3 receptors was able to induce a nearly complete suppression of contractions. The contractions induced by exogenous ACh were competitively antagonized only by atropine (pA2 = 9.01 ± 0.05). M3 selective antagonist, up to 10(-6) m, caused a moderate concentration-dependent rightward shift of ACh curve (pA2 = 7.96 ± 0.10). These data show that M3 muscarinic receptors possess a central role in mediating cholinergic contraction of horse bronchi, while M1 and M2 receptors seem to have a cooperative role. Selective muscarinic antagonists seem unlikely to be useful against bronchoconstriction associated with airway diseases in horses. Conversely, compounds with selectivity for both M1 and M3 receptors could be as effective as traditional anticholinergics and induce fewer cardiac side effects.

OBJECTIVE To evaluate the effect of intraurethral administration of atracurium besylate for urinary obstruction resulting from urethral plugs in male cats. METHODS Forty-five male cats were divided into the treatment group (n=25), in which 4 mL atracurium besylate solution (0·5 mg/mL) was injected into the urethral lumen, and the control group (n=20), treated with saline. All cats were then submitted to retrograde flushing until the removal of the occlusion was obtained. RESULTS The percentage of cats in which the plug was removed at the first attempt was significantly (P<0·05) higher in the treatment group (64%) than in the control group (15%). Moreover, the mean (±SD) time required for the removal of the urethral obstruction was significantly shorter in the treatment group than in the control group (21·1 ±16·2 seconds versus 235·2 ±132·4 seconds; P<0·001). CLINICAL SIGNIFICANCE The results of this study indicate that in adult male cats with urethral plugs, urethral administration of atracurium besylate increases the proportion of animals in which the obstruction is removed at the first attempt and reduces the time required to remove the urethral plugs.

Background: Remote ischemic preconditioning (remote IPC) induced by short non-deleterious ischemic episodes prior to an index ischemic event is known to protect the heart from lethal myocardial ischemia-reperfusion (I/R) injury.Although demonstrated to be effective across almost all species, the underlying signaling pathways and specifically a role for nitric oxide (NO) remain poorly understood.We and others recently showed that brief episodes of limb I/R via blood pressure cuff in-/deflations increases endothelial NO synthase (eNOS) activity with a subsequent formation of NO, nitroso species (RNO) and nitrite.Nitrite, in turn, has been shown to protect the myocardium from lethal ischemia-reperfusion when activated by the heme globin myoglobin (Mb).We therefore hypothesized that remote IPC initiates the release of NO species in an eNOS-dependent manner, and that Mb is required to reduce this endogenously formed species to NO to protect the myocardium.Methods and Results: This study was conducted using a mouse model of remote IPC followed by open-chest I/R via reversible ligation of the left coronary artery in vivo.Four cycles of remote IPC consisting of 5 minutes of hindlimb ischemia followed by 5 minutes of reperfusion, checked by laser Doppler perfusion imaging, caused a release of NO, RNO and nitrite into the circulation.Remote IPC furthermore stimulated a post-translational modification of mitochondrial complex I by S-nitrosation and a subsequent decrease in reactive oxygen species in the reperfused myocardium.This finally caused a reduction in myocardial infarct size per area at risk from 36±2% to 17±1% in wild-types (n=5,p<0.0001).Targeted disruption of endothelial nitric oxide synthase in eNOS-/-mice impaired the release of NO species during remote IPC and completely abolished the beneficial effects on myocardial necrosis (control vs. remote IPC: 45±3% vs. 41±3%, p=n.s.).Finally, in Mb-deficient mice (Mb-/-) remote IPC caused an increase in NO species, but was without effects on infarct size (control vs. remote IPC: 31±1% vs. 35±2% p=n.s.).All values are means±SEM. Conclusion:A concerted action between vascular and myocardial signaling pathways is involved in the NO triggered protection from remote ischemic preconditioning.While eNOS is essentially required for the formation of circulation NO species as triggering mechanisms, Mb in the heart is required for the activation of nitrite to nitric oxide leading to protection of the myocardium at risk.