Administration Of Adenosine Triphosphate Research Articles

Pd/Pa fluctuation with continuous ATP administration indicates inaccurate FFR measurement caused by insufficient hyperemia.

Continuous intravenous adenosine triphosphate (ATP) administration is the standard method for inducing maximal hyperemia in fractional flow reserve (FFR) measurements. Several cases have demonstrated fluctuations in the ratio of mean distal coronary pressure to mean arterial pressure (Pd/Pa) value during ATP infusion, which raised our suspicions of FFR value inaccuracy. This study aimed to investigate our hypothesis that Pd/Pa fluctuations may indicate inaccurate FFR measurements caused by insufficient hyperemia. We examined 57 consecutive patients with angiographically intermediate coronary lesions who underwent fractional flow reverse (FFR) measurements in our hospital between November 2016 and September 2018. Pd/Pa was measured after continuous ATP administration (150μg/kg/min) via a peripheral forearm vein for 5min (FFRA); and we analyzed the FFR value variation in the final 20s of the 5min, defining 'Fluctuation' as variation range > 0.03. Then, 2mg of nicorandil was administered into the coronary artery during continued ATP infusion, and the Pd/Pa was remeasured (FFRA+N). Fluctuations were observed in 23 of 57 patients. The cases demonstrating discrepancies of > 0.05 between FFRA and FFRA+N were observed more frequently in the fluctuation group than in the non-fluctuation group (12/23 vs. 1/34; p < 0.0001). The discrepancy between FFRA and FFRA+N values was smaller in the non-fluctuation group (mean difference ± SD; -0.00026 ± 0.04636 vs. 0.02608 ± 0.1316). Pd/Pa fluctuation with continuous ATP administration could indicate inaccurate FFR measurements caused by incomplete hyperemia. Additional vasodilator administration may achieve further hyperemia when Pd/Pa fluctuations are observed.

PM2.5 Exposure Inhibits Transepithelial Anion Short-circuit Current by Downregulating P2Y2 Receptor/CFTR Pathway.

Fine particulate matter (PM2.5) can damage airway epithelial barriers. The anion transport system plays a crucial role in airway epithelial barriers. However, the detrimental effect and mechanism of PM2.5 on the anion transport system are still unclear. In this study, airway epithelial cells and ovalbumin (OVA)-induced asthmatic mice were used. In transwell model, the adenosine triphosphate (ATP)-induced transepithelial anion short-circuit current (Isc) and airway surface liquid (ASL) significantly decreased after PM2.5 exposure. In addition, PM2.5 exposure decreased the expression levels of P2Y2R, CFTR and cytoplasmic free-calcium, but ATP can increase the expressions of these proteins. PM2.5 exposure increased the levels of Th2-related cytokines of bronchoalveolar lavage fluid, lung inflammation, collagen deposition and hyperplasisa of goblet cells. Interestingly, the administration of ATP showed an inhibitory effect on lung inflammation induced by PM2.5. Together, our study reveals that PM2.5 impairs the ATP-induced transepithelial anion Isc through downregulating P2Y2R/CFTR pathway, and this process may participate in aggravating airway hyperresponsiveness and airway inflammation. These findings may provide important insights on PM2.5-mediated airway epithelial injury.

Protective effect of adenosine triphosphate and benidipine separately or together against cardiotoxicity caused by bevacizumab

ABSTRACT Bevacizumab is a recombinant humanized monoclonal antibody whose adverse effects include cardiotoxicity. We investigated whether using adenosine triphosphate (ATP) or benidipine either separately or together protects against cardiac damage induced by bevacizumab in rats. Forty Wistar albino male rats were allocated to five groups of eight: bevacizumab (Bv), ATP + bevacizumab (ABv), benidipine + bevacizumab (BBv), ATP + benidipine + bevacizumab (ABBv) and untreated controls. Rats in the ABv group were injected intraperitoneally (i.p.) with 2 mg/kg ATP. The BBv group was given 4 mg/kg benidipine by oral gavage. The ABBv group was injected i.p. with 2 mg/kg ATP and simultaneously administered 4 mg/kg benidipine orally. One hour after administration of ATP, benidipine or normal saline, the Bv, ABv, BBv and ABBv groups were injected i.p. with 10 mg/kg bevacizumab. Malondialdehyde (MDA) and total glutathione (tGSH) levels were measured in cardiac tissue, and troponin I (TP I) and creatine kinase MB (CK-MB) levels were measured in blood samples. Tissue samples were examined for histopathology. We found the lowest TP I, CK-MB and MDA levels and the highest tGSH level in the ABBv group; these results were similar to the control group. Nuclei of cardiomyocytes in the BV group were misshapen and shrunken, and myofibers were disrupted; we also observed eosinophilic degeneration and interstitial edema. Blood capillaries were dilated and congested. We observed amelioration of these findings in the ABBv group. We found that ATP and benidipine alone or in combination reduced cardiac damage associated with the use of bevacizumab. ATP + benidipine combined therapy produced the most favorable results.

TMET-38. LOSS OF FUNCTION OF CDK7 IS SYNTHETICALLY LETHAL WITH FATTY ACID OXIDATION INHIBITION IN GLIOBLASTOMA

Abstract CDK7 has been identified as a potential drug target for glioblastoma (GBM), a highly lethal primary brain tumor. However, resistance to therapy develops quickly, which may be facilitated by drug-induced reprogramming of metabolism. By combination of a transcriptome and metabolite screening analyses followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we demonstrated that both genetic and pharmacological (YKL-5-124 and THZ1) CDK7 inhibition elicited substantial metabolic reprogramming. Specifically, CDK7i elicited an increase of oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO) manifested by enhanced labeling of citric acid cycle intermediates from palmitic acid. Consistently, the combination treatment of CDK7i inhibitors with blockers of FAO (etomoxir) or cellular respiration (gamitrinib) exerted substantial synergistic growth inhibition in patient derived xenograft as well as neurosphere GBM cultures, which was mainly driven by a collapse of oxidative energy metabolism. In turn, exogenous administration of adenosine triphosphate partially rescued from the cell death induced by the combination treatment. Moreover, the combination treatment activated intrinsic apoptosis through a reduction of both Mcl-1 and Bcl-xL as demonstrated by rescue experiments. Finally, the combined administration of YKL-5-124 and etomoxir extended overall in an orthotopic patient-derived xenograft model of GBM. In summary, these data support that simultaneous targeting of CDK7 and FAO might be a potential novel therapy against GBM.

Distribution and Function of Platelet-derived Growth Factor Receptor Alpha-positive Cells and Purinergic Neurotransmission in the Human Colon: Is It Different Between the Right and Left Colon?

Background/AimsPlatelet-derived growth factor receptor alpha-positive (PDGFRα+) cells function in the purinergic regulation of gastrointestinal motility, and purines are reportedly inhibitory neurotransmitters in the enteric nervous system. We explore the distribution and function of PDGFRα+ cells related to purinergic inhibitory neurotransmission in human right and left colons.MethodsHuman colonic segments were prepared with mucosa and submucosa intact, and the circular muscle tension and longitudinal muscle tension were recorded. Purinergic neurotransmitters were administered after recording the regular contractions. Immunohistochemistry was performed on the circular muscle layers. Intracellular recording was performed on the colonic muscular layer. SK3, P2RY1, and PDGFR-α mRNA expression was tested by quantitative real-time polymerase chain reaction (qPCR).ResultsAdenosine triphosphate (ATP) treatment significantly decreased the frequency and area under the curve (AUC) of the segmental contraction in right and left colons. Beta-nicotinamide adenine dinucleotide (β-NAD) decreased the frequency in the right colon and the amplitude, frequency and AUC in the left colon. Apamin significantly increased frequency and AUC in the left colon, and after apamin pretreatment, ATP and β-NAD did not change segmental contractility. Through intracellular recordings, a resting membrane potential decrease occurred after ATP administration; however, the degree of decrease between the right and left colon was not different. PDGFRα+ cells were distributed evenly in the circular muscle layers of right and left colons. SK3, P2RY1, and PDGFRα expression was not different between the right and left colon.ConclusionPurines reduce right and left colon contractility similarly, and purinergic inhibitory neurotransmission can be regulated by PDGFRα+ cells in the human colon.

ПРОГНОСТИЧЕСКОЕ ЗНАЧЕНИЕ ФУНКЦИОНАЛЬНОЙ ПРОБЫ МОЗГОВОГО КРОВОТОКА С АДЕНОЗИНТРИФОСФАТОМ ПО ДАННЫМ ОФЭКТ С 99mTc-ГМПАО У ПАЦИЕНТОВ С АТЕРОСКЛЕРОЗОМ СОННЫХ АРТЕРИЙ

Introduction: Previously, a functional test with intravenous administration of adenosine triphosphate (ATP) was proposed to assess the reactivity of cerebral circulation and the functional significance of internal carotid artery stenoses, with evaluation by brain SPECT (neuroSPECT) with 99mTc-HMPAO. The types of the reaction of the cerebral blood flow during it were identified, with different ratios of internal carotid artery stenoses and the degree of ischemic brain damage assessed according to brain MRI data. However, the prognostic value of the results of the ATP test of cerebral blood flow in relation to disorders of cerebral circulation (NMC) remains unknown. Purpose: In a retrospective study, we tried to study the prognostic value of the ATP test of cerebral blood flow in relation to the risk of subsequent disorders of cerebral circulation. Material and methods: The retrospective study included 37 patients with atherosclerotic stenosis of the carotid arteries, who in 2002–2005 underwent functional studies of cerebral blood flow with a sample with intravenous administration of ATP solution. Brain damage was quantified according to MRI data (Magnetom Open, Siemens) in a T2-weighted mode, according to a previously developed technique. Denoting Iliq – the intensity of the T2 signal from the cerebrospinal fluid in the ventricles of the brain, Iinsult – in the area affected by ischemia, and Inorm – in the area of the unaffected brain, the volume of the damaged tissue (VDT) was calculated as the sum taken from all sections i, where the area of brain damage is visible: VDT=Σid·Si∙[(Iinsult ‒ Inorm)/(Iliq ‒ Inorm)]i, where d is the thickness of the slice, and Si is the area of the ischemia area on the slice i. The quota of damaged tissue in the physical volume of the lesion area is then obviously eqal to : QD={Σid·Si∙[(Iinsult ‒ Inorm)/(Iliq ‒ Inorm)]i}/{Σid·Si}. NeuroSPECT with 99mTc-HMPAO (540 MBq) in each patient was carried out at rest and with intravenous administration of ATP solution (100 μg / kg of weight, intravenously slowly for 1 min under ECG control). The asymmetry of the cerebral blood flow was evaluated at rest and in a sample with ATP as the 99mTc-HMPAO accumulation asymmetry index (AI) – the interhemispheric ratio of the average 99mTc-HMPAO absorption score in the middle cerebral artery basin. Results: In accordance with the previously presented classification, patients were assigned to one of three groups – with different types of brain blood flow reaction to a stress test with ATP. In 14 individuals (type 1), a symmetrical distribution of blood flow at rest was noted (AI=0.98±0.01), while the ATP test caused an asymmetry in the uptake of 99mTc-HMPAO (AI=0.91±0.04), due to a decrease on the side of the stenosis-dependent hemisphere (unilateral stenosis of the common and/or internal carotid arteries, exceeding 55 %), without signs of damage to the cerebral cortex. In 11 patients with previous ischemic brain injuries (type 2), proven by MRI, the carotid arteries were patent, including after carotid endarterectomy (5 patients) or after correction of stenosis with a stent (three). Rest asymmetry of blood flow was present (AI=0.92±0.03). The ATP test increased blood supply on the side of injury if, according to T2-weighted MRI in the ischemic area, QD&lt;0.35. Due to this, in general, there was a significant decrease in the absorption asymmetry of 99mTc-HMPAO (AI=0.96±0.03) during the ATP test. In 12 patients (type 3) with predominantly unilateral 50‒90 % carotid artery stenosis and ischemic stroke on the same side (group III), the hemispheric asymmetry of blood supply to the brain, noted already at rest (AI=0.96±0.03), increased (AI=0.93±0.03) with an adenosine test. When analyzing the results of a two-year follow-up, it turned out that frequent transient ishemic attacs, minor strokes and strokes developed only in patients in whom the adenosine test induced or increased the interhemispheric asymmetry of 99mTc-HMPAO accumulation by more than 5 % – four with type 1 reactivity, and three with type 3 reactivity Conclusions: Thus, perfusion neuroSPECT with 99mTc-HMPAO and ATP stress-test can be employed to identify patients with a reduced reserve of cerebral perfusion, who have an increased risk of ischemic stroke. Quantitative analysis of T2-weighted MRI gives an estimate of the proportion of viable brain tissue in the focus of the past ischemia, in which reactivity is preserved.

Adenosine Triphosphate Exerts Cardioprotective Effect on High-Dose Atorvastatin-Induced Heart Damage in Rats

Atorvastatin is a statin derivated hypolipidemic drug used in the treatment of hyperlipidemia. High-dose atorvastatin has been shown to significantly reduce adenosine triphosphate (ATP) levels in the heart tissue. Reduction of ATP by atorvastatin causes increased production of reactive oxygen species (ROS), decreased antioxidants, subsequent cell membrane and mitochondrial damage. The present study aimed to biochemically investigate the protective effect of ATP against possible cardiac damage caused by high dose atorvastatin in rats. Male Wistar rats were divided into atorvastatin (ATR), atorvastatin+ATP (AAT) and healthy control (HG) groups. ATP at a 25 mg/kg dose was injected intraperitoneally (ip) to the AAT (n-6) group. 0.9% NaCl as solvent was applied to the ATR (n-6) and HG (n-6) groups by the same route. Afterward, atorvastatin was administered orally at a dose of 20 mg/kg to the AAT and ATR groups. This procedure was repeated once daily for four weeks. At the end of this period, blood samples were taken into tubes to analyze troponin-I (TP-I) by cardiac puncture before animals were sacrificed with high-dose anesthesia. In addition, heart tissues were removed and malondialdehyde (MDA), total glutathione (tGSH), total oxidant (TOS) and total antioxidant (TAS) levels were measured. Biochemical test results showed that in the heart tissues of the ATR group, the oxidative parameters MDA and TOS significantly increased, while the antioxidant parameters tGSH and TAS significantly decreased compared to AAT and HG. Atorvastatin alone administration significantly increased blood TP-I levels, a marker of cardiac tissue damage. However, ATP administration to AAT group animals brought oxidative parameter levels closer to HG, despite high-dose atorvastatin treatment. In addition, the significant decrease in antioxidant levels was prevented by ATP application. High doses of atorvastatin can cause heart damage. ATP treatment was able to prevent atorvastatin-induced oxidative heart damage.

Long-term outcome of adenosine-induced atrial fibrillation after atrial fibrillation ablation: A propensity score matching analysis.

Nonpulmonary vein (non-PV) foci, in addition to pulmonary vein (PV), are considered important in initiating atrial fibrillation (AF). This study investigates the adenosine triphosphate (ATP) as a method for inducing non-PV ectopy. The study cohort consisted of 1388 patients with AF (728 with paroxysmal AF, 650 with nonparoxysmal AF) who underwent catheter ablation. To confirm dormant PV conductions and non-PV foci, 20 or 40mg ATP was administered intravenously at the end of the procedure. The ATP test induced AF in 36 of 1388 (2.6%) patients, in whom two (6%) had ectopy arising from the both atria, 15 (42%) from the right atrium (RA), and five (14%) from left atrium (LA). Because of a lack of reproducibility, the accurate location of non-PV foci was unidentified in the remaining 11 (31%) patients. Additional radiofrequency ablation to non-PV foci induced ATP administration was not performed in 34 patients. Among all 1388 patients, 64 were assigned to the ATP-AF(+) and ATP-AF(-) groups using a propensity score matching analysis (32 patients in each group). During the follow-up period, recurrent AF was observed in 9 of 32 (28%) patients in the ATP-AF(+) group and in 10 of 32 (31%) patients in the ATP-AF(-) group (log-rank p=.84, hazard ratio 0.91 [95% confidence interval 0.36-2.27]). In the univariate analysis, AF induction by ATP test was not predictive of AF recurrence (p=.78). ATP-induced AF was not associated with AF recurrence in the distant period.

Administration of Adenosine Triphosphate Provides Additional Value Over Programmed Electrophysiologic Study in Confirmation of Successful Ablation of Atrioventricular Accessory Pathways.

Objectives: To study the benefit of adenosine triphosphate (ATP) in evaluating ablation endpoints of accessory pathways (AP) and subsequent long-term prognosis.Methods: We reviewed consecutive patients with supraventricular tachycardias due to APs that underwent radiofrequency catheter ablation (RFCA) from January 2016 to September 2018 in our center. The patients were divided into two groups: the ATP group (who had passed both the ATP test and PES after ablation as the endpoint) and the non-ATP group (who had passed PES only after ablation as the endpoint). We reviewed the patients' intra-cardiac electrograms and analyzed their long-term outcomes.Results: In total, 1,343 patients underwent successful RFCA. There were 215 patients in the ATP group with one lost to follow-up. There were 1,128 patients in the non-ATP group with 39 lost to follow-up. Twenty-three patients in the ATP group demonstrated additional electrophysiological entities due to ATP administration, including reappearance of the ablated APs in 16 patients, discovery of PES-undetected APs in 5, induction of atrial fibrillation in 5, premature atrial contractions in 1, and premature ventricular contractions in another. During the 7 to 39 months (average 24.4 ± 9.5 months) follow-up, the recurrence rate was 8.41% (18/214) in the ATP group and 6.80% (74/1,084) in the non-ATP group. In subjects with recurrence, 14 patients (14/18 = 77.8%) in the ATP group and 50 patients (50/74 = 67.6%) in the non-ATP group accepted redo ablations. Among the ATP-group, all the 14 redo APs were the old ones as before. Among the non-ATP-group, redo ablations confirmed that 39 APs were the old ones, while 20 APs were newly detected ones which had been missed previously. The difference in recurrent AP locations confirmed by redo procedures between the two groups was significant (p = 0.008). In the non-ATP group, 20 (40%) of redo cases were proven to have multiple APs, while 33 (3.3%) cases who did not suffer from recurrence had multiple APs. Existences of multiple APs in recurred cases were significantly higher than that in non-recurred ones in the non-ATP group (p < 0.001), while there was no such difference in the ATP group (p = 0.114).Conclusions: The existence of multiple APs was more common in recurrent cases if ATP was not used for confirmation of ablation endpoints. ATP probably has additional value over PES alone by detecting weak AP conductions. ATP can evoke atrial and ventricular arrhythmias.

Characteristics of coronary flow velocity reserve on transthoracic Doppler echocardiography in patients with a history of Kawasaki disease.

The coronary flow velocity reserve of the left anterior descending artery was examined by transthoracic Doppler echocardiography in 189 patients (male 125, female 64) with a history of Kawasaki disease and 10 volunteers (control). Their ages ranged from 6 to 40 years (median 22 years). The patients were divided into nine groups based on the left anterior descending artery lesions. The coronary flow velocity reserve was measured by intravenous administration of adenosine triphosphate (0.15 mg/kg/minute) while fasting. The coronary flow velocity reserve was calculated as the ratio of hyperaemic to basal mean diastolic flow velocities. The respective groups were as follows: control, no coronary artery lesions (n = 39), no coronary artery lesions in the right coronary artery (n = 29), regression (n = 11), aneurysm at the bifurcation of the left coronary artery (n = 26), aneurysm of the left anterior descending artery (n = 15), localised stenosis <75% (n = 12), localised stenosis ≥75% (n = 17), segmental stenosis (n = 5) and coronary artery bypass grafting (n = 36). One-factor ANOVA followed by Tukey's test was used to compare the coronary flow velocity reserve among the groups. The coronary flow velocity reserve was significantly lower in the localised stenosis ≥75%, segmental stenosis and coronary artery grafting groups than in the other groups (p < 0.05). The endothelial function in the epicoronary artery was preserved in patients with a history of Kawasaki disease and dilated coronary artery lesions.

The effect of adenosine triphosphate on propofol-induced myopathy in rats: a biochemical and histopathological evaluation.

Propofol infusion syndrome characterized by rhabdomyolysis, metabolic acidosis, kidney, and heart failure has been reported in long-term propofol use for sedation. It has been reported that intracellular adenosine triphosphate (ATP) is reduced in rhabdomyolysis. The study aims to investigate the protective effect of ATP against possible skeletal muscle damage of propofol in albino Wistar male rats biochemically and histopathologically. PA-50 (n = 6) and PA-100 (n = 6) groups of animals was injected intraperitoneally to 4 mg/kg ATP. An equal volume (0.5 ml) of distilled water was administered intraperitoneally to the P-50, P-100, and HG groups. One hour after the administration of ATP and distilled water, 50 mg/kg propofol was injected intraperitoneally to the P-50 and PA-50 groups. This procedure was repeated once a day for 30 days. The dose of 100 mg/kg propofol was injected intraperitoneally to the P-100 and PA-100 groups. This procedure was performed three times with an interval of 1 days. Our experimental results showed that propofol increased serum CK, CK-MB, creatinine, BUN, TP I, ALT, AST levels, and muscle tissue MDA levels at 100 mg/kg compared to 50 mg/kg and decreased tGSH levels. At a dose of 100 mg/kg, propofol caused more severe histopathological damage compared to 50 mg/kg. It was found that ATP prevented propofol-induced muscle damage and organ dysfunction at a dose of 50 mg/kg at a higher level compared to 100 mg/kg. ATP may be useful in the treatment of propofol-induced rhabdomyolysis and multiple organ damage.

Long-term administration of vitamin B12 and adenosine triphosphate for idiopathic sudden sensorineural hearing loss: a retrospective study.

BackgroundIn idiopathic sudden sensorineural hearing loss (ISSNHL), the relationship between the administration duration of vitamin B12 (vit B12) with adenosine triphosphate (ATP) and their therapeutic effect is not fully understood.ObjectiveTo investigate the therapeutic effect of long-term 16 (≥weeks) administration of vit B12 with ATP on the prognosis of ISSNHL patients and compare it with those of short-term (<8 weeks) and middle-term (≥8 weeks, <16 weeks) administration.MethodsWe retrospectively reviewed the medical records of 117 patients with ISSNHL treated between 2015 and 2018.ResultsThe overall recovery rate was 32.5%. Initial higher hearing threshold and initial higher grade of hearing loss (HL) were associated with a poor prognosis. However, the administration duration of vit B12 and ATP did not influence the overall hearing improvement. With regard to the time course of hearing recovery, there was no significant difference in hearing recovery among the long-, middle-, and short-term administration groups until 16 weeks after treatment. However, at 16–24 weeks after initial treatment, the short-term administration group exhibited significantly lower hearing recovery than did the long-term administration groups.ConclusionsThe administration duration of vit B12 and ATP did not influence the overall hearing prognosis in ISSNHL, but long-term administration of vit B12 and ATP helped prevent the progression of HL after ISSNHL. Our results suggest that long-term administration of vit B12 and ATP is not necessarily required to treat ISSNHL patients, except for slowly progressing HL in the affected ears.

New Algorithm of Stress Echocardiography with Adenosine Triphosphate

Objective. Submaximal myocardial hyperemia is known not to be achieved in 16-18% of cases during cardiac stress tests and monotonic intracubital administration of adenosine triphosphate (ATP) at a dose of 140-160 pg/kg/min. The authors set a task to elaborate a new algorithm for stress echocardiography (SEchoCG) with ATP, providing for the possibility of a stepwise increase in the dosage of the drug, as well as to test it in healthy individuals and patients with coronary heart disease (CHD). Material and methods. The authors elaborated a new algorithm for SEchoCG on the basis of an analysis of the main science databases and their first own experience in using ATP during SEchoCG. The key provisions of the new algorithm were: (a) the exercise test consisted of 3 stages (EchoCG data should be recorded before, during, and 5 minutes after ATP infusion); (b) the criterion for achieving submaximal myocardial hyperemia during ATP administration is a systolic blood pressure (SBP) reduction of 5 and more mm Hg; (c) EchoCG was usually recorded at Stage 2 of the test 3 minutes after the start of ATP administration and with a decline in SBP; (d) the initial dose of ATP administration was 140 pg/kg/min; if SBP did not decrease at 3 minutes of the drug administration, the dosage should be first increased up to 175 pg/kg/ min at 1 minute; if there was no effect, the dosage should be increased up to 210 pg/kg/min at another 2-3 minutes. The algorithm was tested in 9 healthy volunteers, and in 26 patients with CHD. Results. Testing the new algorithm showed that all cases achieved submaximal myocardial hyperemia. SBP decreased below 90 mm Hg in 2 patients; 1 patient developed second-degree atrioventricular block; however, a simple decrease in the ATP infusion rate within 30 sec leveled this symptomatology. The SEchoCG data acceptable for the subsequent analysis of myocardial contractility and deformation could be recorded in all the examinees. Conclusion. The new algorithm for SEchoCG with ATP is effective in recording EchoCG findings. To have a final decision on the safety and information value of a new stress test protocol, it may be recommended to further test those in larger groups of patients during SEchoCG and in the use of other imaging procedures to assess myocardial contractility and perfusion.

Discordance predictor between fractional flow reserve and resting full-cycle ratio in clinical characteristics

Abstract Introduction Fractional flow reserve (FFR) is a gold standard method to evaluate functional lesion severity in daily clinical practice. Recently, the resting full-cycle ratio (RFR) which was newly developed resting indices was launched. Unlike other resting indices evaluated in diastolic phase, RFR is evaluated during entire cardiac phase. Previous studies showed discordance predictors between FFR and instantaneous wave-free ratio. However, it is previously unreported what predictor cause discordant outcome between FFR and RFR. Purpose The purpose of this study was to evaluate clinical predictors of discordance between FFR and RFR. Methods A total of 156 patients with 220 lesions were prospectively enrolled in this study. RFR was evaluated before inducing hyperemia. FFR was measured after intravenous adenosine triphosphate administration (180 mcg/kg/min). According to FFR and RFR values, the patients and lesions were classified into 4 groups: Concordant negative (Group-1 [n=114]: FFR &amp;gt;0.80, RFR &amp;gt;0.89); negative FFR and positive RFR (Group-2 [n=18]: FFR &amp;gt;0.80, RFR ≤0.89); positive FFR and negative RFR (Group-3 [n=25]: FFR ≤0.80, RFR &amp;gt;0.89); Concordant positive (Group-4 [n=63]: FFR ≤0.80, RFR ≤0.89). Among them, discordance predictors with clinical characteristics between RFR and FFR were compared using by two separate logistic regression analyses. (Group-1 vs. Group-2, Group-3 vs. Group-4, respectively). Age, sex and those predictors with a p value ≤0.10 were included in a multivariate regression analysis using by forward stepwise selection to identify independent predictors of discordance. Results On multiple regression analysis, hemodialysis (HD) (OR:6.072 [1.090–33.836]), peripheral artery disease (PAD) (OR:9.053 [1.776–46.162]) and left anterior descending artery (LAD) (OR:9.264 [2.092–41.031]) were significantly associated with positive RFR among negative FFR groups (Groupe 2 discordance). Conversely, diabetes mellitus (DM) (OR:0.212 [0.062–0.721]) and Hb (OR:1.480 [1.102–1.987]) were significantly associated with negative RFR among positive FFR groups (Groupe 3 discordance) Conclusions Since the clinical characteristics with HD, PAD, LAD, DM and Hb may influence concordant with FFR during RFR evaluation, it should be considered when interpreting RFR. Distribution and independent predictors Funding Acknowledgement Type of funding source: None

Protective effect of adenosine triphosphate against sunitinib-related skin damage in rats.

Cutaneous side effects associated with sunitinib use are a major problem in patients receiving cancer treatment. The aim of this study was to investigate the protective effect of adenosine triphosphate (ATP) against possible skin damage resulting from sunitinib use in rats. Thirty Albino Winstar rats were divided into the following three groups: healthy controls (HCs, n = 10), sunitinib (SUN, n = 10), and sunitinib + ATP (SAT, n = 10). ATP was injected intraperitoneally at a dose of 2 mg/kg. One hour subsequent to the administration of ATP and 0.9% NaCl, the SAT and SUN groups were orally administered a dose of 25 mg/kg sunitinib to the stomach. Macroscopic evaluation of the skin indicated lower levels of skin damage in the SAT group than in the SUN group. As an indicator of oxidative stress, malondialdehyde (MDA), total oxidant status (TOS), and oxidative stress index (OSI) levels were significantly higher in the SUN group than in the HC group, while total glutathione (tGSH) and total antioxidant status (TAS) levels were significantly lower. However, MDA, TOS, and OSI levels were significantly lower in the SAT group than in the SUN group, while tGSH and TAS levels were significantly higher. Histopathological examination revealed keratin plugs with edema, vasopathology, and inflammatory cell infiltration in the SUN group. The SAT group showed less necrotic epithelium, keratin plugs, edema, and vasopathology than the SUN group. ATP can be effective in preventing skin damage caused by sunitinib use by reducing oxidative stress.

Effect of QTU prolongation on hyperemic instantaneous wave-free ratio value: a prospective single-center study

We hypothesized that in patients with QT prolongation, resistance might not decrease in the wave-free period, because QTU prolongation cannot be detected by instantaneous wave-free ratio (iFR) analysis software. We investigated whether corrected QTU (QTUc) prolongation affects the hyperemic iFR value. Forty-two consecutive patients with intermediate stenosis (≥ 50%) in the left anterior descending coronary artery (LAD) were analyzed. Fractional flow reserve (FFR) and hyperemic iFR were simultaneously and continuously recorded with intravenous adenosine triphosphate (ATP) and papaverine infusions. In 17 patients with stenosis in the proximal LAD, coronary flow was measured. Patients were divided into two groups according to the median absolute deviation of the QTUc by ATP administration/QTUc by papaverine administration. FFR, hyperemic iFR, and flow data were compared between each stimulus and group. Moreover, influences of pressure and electrocardiogram parameters on differences in iFR values under ATP and papaverine administration were compared between the following two groups (group 1: the absolute difference of hyperemic iFR values between ATP and papaverine administration is ≤ 0.05; group 2: that is > 0.05). The paired t test and t test were used in analysis. Hyperemic iFR values of patients under the use of papaverine were lower than those of patients under the use of ATP when QTUc was more prolonged by papaverine administration than by ATP administration (ATP 0.74 ± 0.14, papaverine 0.71 ± 0.15, P = 0.025). No significant differences were observed in the FFR value and flow data between the groups. Regarding QTU, QTUc, and QTUc by ATP/QTUc by papaverine, significant differences were observed between group 1 and group 2. Pressure parameters did not induce significant differences. QTUc prolongation induced by papaverine was associated with lower hyperemic iFR values. An iFR-based assessment might lead to inappropriate treatment of patients with QTUc prolongation.

Acid sphingomyelinase plays a critical role in LPS- and cytokine-induced tissue factor procoagulant activity

AbstractTissue factor (TF) is a cofactor for factor VIIa and the primary cellular initiator of coagulation. Typically, most TF on cell surfaces exists in a cryptic coagulant-inactive state but are transformed to a procoagulant form (decryption) following cell activation. Our recent studies in cell model systems showed that sphingomyelin (SM) in the outer leaflet of the plasma membrane is responsible for maintaining TF in an encrypted state in resting cells, and the hydrolysis of SM leads to decryption of TF. The present study was carried out to investigate the relevance of this novel mechanism in the regulation of TF procoagulant activity in pathophysiology. As observed in cell systems, administration of adenosine triphosphate (ATP) to mice enhanced lipopolysaccharide (LPS)-induced TF procoagulant activity in monocytes. Treatment of mice with pharmacological inhibitors of acid sphingomyelinase (ASMase), desipramine and imipramine, attenuated ATP-induced TF decryption. Interestingly, ASMase inhibitors also blocked LPS-induced TF procoagulant activity without affecting the LPS-induced de novo synthesis of TF protein. Additional studies showed that LPS induced translocation of ASMase to the outer leaflet of the plasma membrane and reduced SM levels in monocytes. Studies using human monocyte-derived macrophages and endothelial cells further confirmed the role of ASMase in LPS- and cytokine-induced TF procoagulant activity. Overall, our data indicate that LPS- or cytokine-induced TF procoagulant activity requires the decryption of newly synthesized TF protein by ASMase-mediated hydrolysis of SM. The observation that ASMase inhibitors attenuate TF-induced coagulation raises the possibility of their therapeutic use in treating thrombotic disorders associated with aberrant expression of TF.

Effects of ATP administration on isolated swine hearts: Implications for ex vivo perfusion and cardiac transplantation.

Cardiac transplant outcomes can be compromised by the effects of global ischemia and associated reperfusion injury. In attempts to alleviate these phenomena, various pharmaceutical agents can be administered. Previous reports have shown that adenosine triphosphate (ATP) may act as either a postconditioning (PoC) or supplementary (Sup) therapy with cardiosupportive benefits. To further evaluate ATP’s relative effectiveness, we used an isolated swine heart four-chamber working model to monitor both hemodynamic and metabolic responses. We employed two strategies of ATP administration: (1) a postconditional (PoC) bolus just prior to reanimation, and (2) regular dosing throughout the assessment period (Sup). Ex vivo swine hearts in the Sup group elicited significantly higher left ventricular function during the 2 h monitoring period than controls. In contrast, PoC administration appeared to induce depressed cardiac function. The effects of ATP on cardiac function can have varied effects, dependent on when it is administered. Impact statement We employed an isolated swine heart four-chamber working model to investigate two potential strategies for adenosine triphosphate (ATP) administration as an ex vivo therapy: (1) application of a single bolus dose during reperfusion (postconditioning or PoC), and (2) repeated bolus dosing throughout the experiment (supplementary or Sup). Ex vivo swine hearts in the Sup group elicited significantly higher left ventricular function during the 2 h experimental monitoring period. In contrast, ATP administration in the PoC group appeared to induce a degree of depressed hemodynamic function. These data suggest varied functional roles of ATP administration relative to their use in ex vivo perfusion strategies. We consider that both treatment strategies, if appropriately administered and with further investigation of dosing paradigms, may eventually elicit value in various clinical scenarios, including heart transplantation and ex vivo heart perfusion to assess potential organs for transplantation and potentially increase the pool of viable donor hearts.

Intravenous administration of adenosine triphosphate and phosphocreatine combined with fluoxetine in major depressive disorder: protocol for a randomized, double-blind, placebo-controlled pilot study

BackgroundMajor depressive disorder (MDD) is a common psychiatric disorder. With systematic antidepressant treatment, 50–75% of patients have a treatment response but require 4–6 weeks to have their symptoms alleviated. Therefore, researchers anticipate the development of novel fast-acting antidepressants. Previous studies have revealed that the decrease of bio-energetic metabolism may contribute to the occurrence of depression, while our team has found adenosine triphosphate (ATP) and phosphocreatine (PCr) to be fast-acting antidepressants in the depressed-animal model. ATP and PCr have already been widely prescribed clinically as energy supplements for cells. This will be the first clinical attempt of the intravenous administration of ATP and PCr combined with orally administered fluoxetine in MDD.MethodsThis is a single-center, randomized, double-blind, placebo-controlled pilot study. A total of 42 patients will be divided randomly into three groups. Patients will receive an intravenous administration of ATP or PCr or saline twice daily combined with orally administered fluoxetine (20 mg/day) for the first 2 weeks and fluoxetine monotherapy for the following 4 weeks. Follow-up assessment will be completed at week 10. Feasibility outcomes will include percentages of patient eligibility, intention to use medication, willingness to participate, drug adherence, completion of the scheduled assessment, retention, drop-out, etc. Physical examination results, Side Effect Rating Scale, adverse events, results from blood tests, electroencephalogram, and electrocardiograph will be recorded for safety evaluation of the augmentation therapy. The trends of efficacy will be evaluated by the reduction rate of the Hamilton Depression Rating Scale, the mean change of the Clinical Global Impression Scale, and the Patients Health Questionaire-9 items.DiscussionIn our study, ATP and PCr will be given by intravenous infusion. Thus patients will be hospitalized for the initial 2 weeks for safety concern. Hospitalization will be an impact factor for the recruitment, participation, drop-out, efficacy, results, etc. The evaluation of our feasibility outcomes, study setting, safety of augmentation therapy and possible efficacy trends among groups, will facilitate a full-scale trial design and sample size calculation.Trial registrationNCT03138681. Registered on 3 May 2017. First patient: 4 May 2017.

Etidronate attenuates tactile allodynia by spinal ATP release inhibition in mice with partial sciatic nerve ligation.

Etidronate is widely used as a therapeutic agent for osteoporosis. We have recently shown that intrathecal administration of etidronate into mice produces an analgesic effect against the capsaicin-induced nociceptive behavior. However, the effect of etidronate on neuropathic pain at the spinal level remains unknown. Therefore, we examined whether etidronate attenuates pain after partial sciatic nerve ligation (PSNL). We evaluated tactile allodynia 7days after PSNL by measuring paw withdrawal with the von Frey filament test. The mRNA and protein levels of SLC17A9 in the ipsilateral lumbar dorsal spinal cord of PSNL-operated mice were determined using real-time PCR and western blotting, respectively. PSNL-induced tactile allodynia was attenuated by oral and intrathecal administration of etidronate, with maximum efficiency at 90 and 60min after injection, respectively. The anti-allodynic effect of intrathecally administered etidronate was completely inhibited by an intrathecal administration of adenosine triphosphate (ATP). The solute carrier family, SLC17, mediates the transport of pain transmitters, like ATP and glutamate. Indeed, we detected several members of the SLC17 family in the mouse dorsal lumbar spinal cord. Among the detected mRNAs, only Slc17a9, encoding for neuronal vesicular ATP transporter, was significantly increased upon PSNL. SLC17A9 protein levels were also significantly increased. In mice subjected to PSNL, SLC17A9 was present in neurons and microglia, but not in astrocytes of the lumbar superficial dorsal horn. Collectively, our results suggest that etidronate produces its anti-allodynic effects by inhibiting SLC17A9-dependent exocytotic ATP release from the dorsal horn in mice subjected to PSNL.