The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain.
To evaluate the short-term safety of ticagrelor when ...compared with clopidogrel in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy.
We conducted a multicenter, randomized, open-label with blinded end point adjudication trial that enrolled 3799 patients (younger than 75 years) with ST-segment elevation myocardial infarction receiving fibrinolytic therapy in 152 sites from 10 countries from November 2015 through November 2017. The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%.
Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). Patients were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel.
The primary outcome was thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days.
The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, and 2177 of 3799 patients (57.3%) were white. At 30 days, TIMI major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel (absolute difference, 0.04%; 95% CI, -0.49% to 0.58%; P < .001 for noninferiority). Major bleeding defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group (absolute difference, -0.18%; 95% CI, -0.89% to 0.54; P = .001 for noninferiority). The rates of fatal (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and clopidogrel groups, respectively. Minor and minimal bleeding were more common with ticagrelor than with clopidogrel. The composite of death from vascular causes, myocardial infarction, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57).
In patients younger than 75 years with ST-segment elevation myocardial infarction, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days.
clinicaltrials.gov Identifier: NCT02298088.
Background and Purpose
Transient receptor potential melastatin type‐8 (TRPM8) is a cold‐sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we reveal the ...molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC).
Experimental Approach
TRPM8 expression and its correlation with the survival rate of CRC patients was analysed. To identify the key pathways and genes related to TRPM8 high expression, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted in CRC patients. TRPM8 functional role was assessed by using Trpm8−/− mice in models of sporadic and colitis‐associated colon cancer. TRPM8 pharmacological targeting by WS12 was evaluated in murine models of CRC.
Key Results
TRPM8 is overexpressed in colon primary tumours and in CD326+ tumour cell fraction. TRPM8 high expression was related to lower survival rate of CRC patients, Wnt–Frizzled signalling hyperactivation and adenomatous polyposis coli down‐regulation. In sporadic and colitis‐associated models of colon cancer, either absence or pharmacological desensitization of TRPM8 reduced tumour development via inhibition of the oncogenic Wnt/β‐catenin signalling. TRPM8 pharmacological blockade reduced tumour growth in CRC xenograft mice by reducing the transcription of Wnt signalling regulators and the activation of β‐catenin and its target oncogenes such as C‐Myc and Cyclin D1.
Conclusion and Implications
Human data provide valuable insights to propose TRPM8 as a prognostic marker with a negative predictive value for CRC patient survival. Animal experiments demonstrate TRPM8 involvement in colon cancer pathophysiology and its potential as a drug target for CRC.
Summary
Heart rate recovery (HRR) is a strong mortality predictor. Exercise training (ET) and β‐blocker therapy have significant impact on the HRR of patients following myocardial infarction (MI). ...However, the combination of ET and β‐blocker therapy, as well as its effectiveness in patients with a more compromised HRR (≤12 bpm), has been under‐studied. Male patients (n = 64) post‐MI were divided: Training + β‐blocker (n = 19), Training (n = 15), β‐blocker (n = 11) and Control (n = 19). Participants performed an ergometric test before and after 3 months of intervention. HRR was obtained during 5 min of recovery and corrected by the cardiac reserve (HRRcorrCR). Compared to pre‐intervention, HRRcorrCR was significantly increased during the 1st and 2nd minutes of recovery in the Training + β‐blocker group (70·5% and 37·5%, respectively; P<0·05). A significant improvement, lasting from the 1st to the 4th minute of recovery, was also observed in the Training group (47%, 50%, 25% and 8·7%, respectively; P<0·05). In contrast, the β‐blocker group showed a reduction in HRRcorrCR during the 2nd and 3rd minutes of recovery (−21·2% and −16·3%, respectively; P<0·05). In addition, interventions involving ET (Training + βb, Training) were significantly more effective in patients with a pre‐intervention HRR ≤ 12 bpm than for patients with HRR > 12 bpm. Combination of β‐blocker therapy with ET does not compromise the effect of training and instead promotes HRR and aerobic capacity improvement. In addition, this combination is particularly beneficial for individuals presenting with a more compromised HRR. However, chronic administration of β‐blocker therapy alone did not promote improvement in HRR or aerobic capacity.
Background and Purpose
N‐Acylethanolamine acid amidase (NAAA) is a lysosomal enzyme accountable for the breakdown of N‐acylethanolamines (NAEs) and its pharmacological inhibition has beneficial ...effects in inflammatory conditions. The knowledge of NAAA in cancer is fragmentary with an unclarified mechanism, whereas its contribution to colorectal cancer (CRC) is unknown to date.
Experimental Approach
CRC xenograft and azoxymethane models were used to assess the in vivo effect of NAAA inhibition. Further, the tumour secretome was evaluated by an oncogenic array, CRC cell lines were used for in vitro studies, cell cycle was analysed by cytofluorimetry, NAAA was knocked down with siRNA, human biopsies were obtained from surgically resected CRC patients, gene expression was measured by RT‐PCR and NAEs were measured by LC–MS.
Key Results
The NAAA inhibitor AM9053 reduced CRC xenograft tumour growth and counteracted tumour development in the azoxymethane model. NAAA inhibition affected the composition of the tumour secretome inhibiting the expression of EGF family members. In CRC cells, AM9053 reduced proliferation with a mechanism mediated by PPAR‐α and TRPV1. AM9053 induced cell cycle arrest in the S phase associated with cyclin A2/CDK2 down‐regulation. NAAA knock‐down mirrored the effects of NAAA inhibition with AM9053. NAAA expression was down‐regulated in human CRC tissues, with a consequential augmentation of NAE levels and dysregulation of some of their targets.
Conclusion and Implications
Our results show novel data on the functional importance of NAAA in CRC progression and the mechanism involved. We propose that this enzyme is a valid drug target for the treatment of CRC growth and development.
Under resting conditions, the failing heart shifts fuel use toward greater glucose and lower free fatty acid (FFA) oxidation. We hypothesized that chronic metabolic abnormalities in patients with ...dilated cardiomyopathy (DCM) are associated with the absence of the normal increase in myocardial glucose uptake and maintenance of cardiac mechanical efficiency in response to pacing stress. In 10 DCM patients and 6 control subjects, we measured coronary flow by intravascular ultrasonometry and sampled arterial and coronary sinus blood. Myocardial metabolism was determined at baseline, during atrial pacing at 130 beats/min, and at 15 min of recovery by infusion of (3)Holeate and (13)Clactate and measurement of transmyocardial arteriovenous differences of oxygen and metabolites. At baseline, DCM patients showed depressed coronary flow, reduced uptake and oxidation of FFA, and preferential utilization of carbohydrates. During pacing, glucose uptake increased by 106% in control subjects but did not change from baseline in DCM patients. Lactate release increased by 122% in DCM patients but not in control subjects. Cardiac mechanical efficiency in DCM patients was not different compared with control subjects at baseline but was 34% lower during stress. Fatty acid uptake and oxidation did not change with pacing in either group. Our results show that in DCM there is preferential utilization of carbohydrates, which is associated with reduced flow and oxygen consumption at rest and an impaired ability to increase glucose uptake during stress. These metabolic abnormalities might contribute to progressive cardiac deterioration and represent a target for therapeutic strategies aimed at modulating cardiac substrate utilization.
Edge illumination x-ray phase contrast tomography is a recently developed imaging technique which enables three-dimensional visualisation of low-absorbing materials. Dedicated phase retrieval ...algorithms can provide separate computed tomography (CT) maps of sample absorption, refraction and scattering properties. In this paper we propose a novel "modified local retrieval" method which is capable of accurately retrieving sample properties in a range of realistic, non-ideal imaging environments. These include system misalignment, defects in the used optical elements and system geometry variations over time due to vibrations or temperature fluctuations. System instabilities were analysed, modelled and incorporated into a simulation study. As a result, an additional modification was introduced to the retrieval procedure to account for changes in the imaging system over time, as well as local variations over the field of view. The performance of the proposed method was evaluated in comparison to a previously used "global retrieval" method by applying both approaches to experimental CT data of a rat's heart acquired in a non-ideal environment. The use of the proposed method resulted in the removal of major artefacts, leading to a significant improvement in image quality. This method will therefore enable acquiring high-resolution, reliable CT data of large samples in realistic settings.
Hyperammonemia during rest periods is a dysfunction in heart failure (HF). The low formation of ammonia during exercise reflects an inefficiency of purine metabolism. Hyperkalemia in response to ...physical exercise is common in HF and may contribute to a contractile inefficiency in type II fibers, leading to early fatigue. We tested the hypothesis that during resistance exercise of high intensity and low volume, this disorder of ammonia metabolism would be more intense, due to the hyperkalemia present in HF.
Alternating resistance exercise (RE) of low intensity and high volume, and high intensity and low volume, were applied to 18 patients with an interval of 7 days between them (functional class II-III New York Heart Association, FE = 33.5 ± 4%) and compared with 22 healthy controls matched for age and gender. Ammonia, potassium and lactate levels were assessed before and immediately after the RE.
Significant differences: Deltas (control vs. HF) in 40% RE: lactate (mg/dl) 26.3 ± 10 vs. 37.7 ± 7; p < 0,001, ammonia (ug/dl) 92.5 ± 18 vs. 48.9 ± 9; p < 0.001. Deltas (control vs. HF) in 80%RE: lactate(mg/dl) 45.0 ± 12 vs. 54.1 ± 11; p < 0.05, ammonia(ug/dl) 133.5 ± 22 vs. 32.2 ± 7; p < 0.001, potassium (mEq/L) 1.6 ± 0.4 vs. 2.0 ± 0.8; p < 0.05. A negative correlation was found between the deltas of ammonia and potassium (r = -0.74, p < 0.001) in the HF group.
We conclude that in HF, there is an inefficiency of purine metabolism that increases with increasing exercise intensity, but not with an increase of total volume. These findings suggest that hyperkalemia may play an important role in the disorders of purine metabolism.
Background Hydroxyethylstarch (HES) is a synthetic polymer of glucose that has been suggested for therapeutic use in long-term plasma expansion. The aim of this study was to test the hypothesis that ...the infusion of a small volume of HES may provide benefits in systemic and regional hemodynamics and metabolism in a brain-dead canine model compared with large volume crystalloid resuscitation. Methods Fourteen mongrel dogs were subjected to a brain-death protocol by consecutive insufflations of a balloon catheter in the epidural space. One hour after induction of brain-death, the animals were randomly assigned to two groups: NS (0.9% NaCl, 33mL/kg), and HES (6%HES 450/0.7, 17mL/Kg). Systemic and regional hemodynamics were evaluated using Swan-Ganz, ultrasonic flowprobes, and arterial catheters. Serial blood samples were collected for blood gas, electrolyte, and serum chemistry analysis. Systemic, hepatic, and splanchnic O2 -derived variables were also calculated. Results Epidural balloon insufflations induced a significant increase in mean arterial pressure, cardiac output (MAP and CO, respectively), regional blood flow, and systemic vascular resistance. Following the hyperdynamic phase, severe hypotension with normalization of systemic and regional blood flow was observed. Fluid resuscitation induced a prompt increase in MAP, CO, and portal vein blood flow, and a significant reduction in systemic and pulmonary vascular resistance. There were no differences between groups in metabolic indices, liver function tests (LFTs), or renal function tests. HES was more effective than NS in restoring cardiac performance in the first 2h after fluid resuscitation ( P < 0.05). Both tested solutions partially and temporarily restored systemic and regional oxygen delivery. Conclusion Small volumes of 6% HES 450/0.7 improved cardiovascular performance and provided the same regional hemodynamic and metabolic benefits of large volumes of isotonic crystalloid solutions.
Background:
Cardiovascular comorbidities such as hypertension and inflammatory response dysregulation are associated with worse COVID-19 prognoses. Different cytokines have been proposed to play ...vital pathophysiological roles in COVID-19 progression, but appropriate prognostic biomarkers remain lacking. We hypothesized that the combination of immunological and clinical variables at admission could predict the clinical progression of COVID-19 in hypertensive patients.
Methods:
The levels of biomarkers, including C-reactive protein, lymphocytes, monocytes, and a panel of 29 cytokines, were measured in blood samples from 167 hypertensive patients included in the BRACE-CORONA trial. The primary outcome was the highest score during hospitalization on the modified WHO Ordinal Scale for Clinical Improvement. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and biomarkers associated significantly with the primary outcome.
Results:
During hospitalization, 13 (7.8%) patients showed progression to more severe forms of COVID-19, including three deaths. Obesity, diabetes, oxygen saturation, lung involvement on computed tomography examination, the C-reactive protein level, levels of 15 cytokines, and lymphopenia on admission were associated with progression to severe COVID-19. Elevated levels of interleukin-10 and interleukin-12 (p70) combined with two or three of the abovementioned clinical comorbidities were associated strongly with progression to severe COVID-19. The risk of progression to severe disease reached 97.5% in the presence of the five variables included in our model.
Conclusions:
This study demonstrated that interleukin-10 and interleukin-12 (p70) levels, in combination with clinical variables, at hospital admission are key biomarkers associated with an increased risk of disease progression in hypertensive patients with COVID-19.
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