Circulation最新文献

Background: The MINT trial (Myocardial Ischemia and Transfusion) raised concern for harm from a restrictive versus liberal transfusion strategy in patients with acute myocardial infarction (MI) and anemia. Type 1 and type 2 MI are distinct pathophysiologic entities that may respond differently to blood transfusion. This analysis sought to determine whether the effects of transfusion varied among patients with a type 1 or a type 2 MI and anemia. The authors hypothesized that the liberal transfusion strategy would be of greater benefit in type 2 than in type 1 MI.

Methods: The authors compared rates of death or MI at 30 days in patients with type 1 (n=1460) and type 2 (n=1955) MI and anemia who were randomly allocated to a restrictive (threshold, 7-8 g/dL) or a liberal (threshold, 10 g/dL) transfusion strategy.

Results: The primary outcome of death or MI was observed in 16% of type 1 MI and 15.4% of type 2 MI patients. The rate of death or MI was higher in patients with type 1 MI randomized to a restrictive (18.2%) versus liberal (13.8%) transfusion strategy (relative risk [RR], 1.32 [95% CI, 1.04-1.67]) with no difference observed between the restrictive (15.8%) and liberal (15.1%) transfusion strategies in patients with type 2 MI (RR, 1.05 [95% CI, 0.85-1.29]). The test for a differential effect of transfusion strategy by MI type was not statistically significant (P_interaction = 0.16).

Conclusions: The concern for harm with a restrictive transfusion strategy in patients with acute MI and anemia raised in the MINT primary outcome manuscript may be more apparent in patients with type 1 than type 2 MI.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02981407.

Drowning is the third leading cause of death from unintentional injury worldwide, accounting for 7% of all injury-related deaths. The World Health Organization estimates that there are ≈236 000 deaths due to drowning worldwide each year. Significant efforts have focused on creating systems to prevent drowning, but an average of 4000 fatal and 8000 nonfatal drownings still occur annually in the United States-likely an underestimate. Drowning generally progresses from initial respiratory arrest due to submersion-related hypoxia to cardiac arrest; thus, it can be challenging to distinguish respiratory arrest from cardiac arrest because pulses are difficult to accurately palpate within the recommended 10-second window. Therefore, resuscitation from cardiac arrest attributable to this specific circumstance must focus on restoring breathing as much as it does circulation. Resuscitation from drowning may begin with in-water rescue breathing when safely provided by rescuers trained in the technique and should continue with chest compressions, in keeping with basic life support guidelines, once the drowned individual and the rescuer are in a safe environment (eg, dry land, a boat). This focused update incorporates systematic reviews from 2021 to 2023 performed by the International Liaison Committee on Resuscitation related to the resuscitation of drowning. These clinical guidelines are the product of a committee of experts representing the American Heart Association and the American Academy of Pediatrics. The writing group reviewed the recent International Liaison Committee on Resuscitation systematic reviews, including updated literature searches, prior guidelines related to resuscitation from cardiac arrest following drowning, and other drowning-related publications from the American Heart Association and American Academy of Pediatrics. The writing group used these reviews to update its recommendations aimed at resuscitation of cardiac arrest following drowning in adults and children.

Background: Ca²⁺ release-activated Ca²⁺ channel regulator 2A (CRACR2A) has been linked to immunodeficiency attributable to T-cell dysfunction in humans. We discovered that neutrophil CRACR2A promotes neutrophil adhesive and migratory functions by facilitating Ca²⁺ mobilization and β2 integrin activation.

Methods: Myeloid-specific cracr2a conditional knockout mice and intravital microscopy were used to investigate the physiologic role of neutrophil cracr2a in neutrophil recruitment in vascular inflammation. Cracr2a-deficient neutrophils or dHL-60 (differentiated human neutrophil-like) cells and CRACR2A-derived peptides were used in flow cytometry, immunoprecipitation, cytosolic Ca²⁺ mobilization, and flow chamber assays to elucidate the molecular mechanism. Four-dimensional confocal intravital microscopy of mice after focal brain ischemia and single neutrophil behavioral analysis demonstrated the pathologic role of neutrophil cracr2a in brain damage.

Results: Compared with wild-type control mice, cracr2a conditional knockout mice exhibited significantly reduced adhesion, crawling, and transmigration of neutrophils on ear and cremaster venules in tumor necrosis factor-α-induced sterile inflammation. Neutrophil cracr2a rapidly interacts with STIM1 (stromal interaction molecule 1) after agonist stimulation and facilitates Ca²⁺ mobilization, increasing the ligand-binding function of β2 integrin. Our findings in cracr2a-deficient mouse neutrophils are recapitulated in dHL-60 cells, in which CRACR2A is deleted by CRISPR/Cas9. Furthermore, overexpression of CRACR2A in CRACR2A KO dHL-60 cells restores normal function. Using a series of peptides covering the coiled-coil region of CRACR2A, we identified a palmitoylated 20-mer that blocks STIM1-CRACR2A interaction. Treating neutrophils with this 20-mer inhibits Ca²⁺ mobilization and β2 integrin activation after agonist stimulation, reducing neutrophil recruitment to an activated endothelial cell monolayer under venous shear stress and to ear venules in tumor necrosis factor-α-challenged mice. Cerebral 4-dimensional intravital microscopy of mice after focal brain ischemia revealed that neutrophil cracr2a enhances the emergence of highly migratory neutrophils by increasing the surface level of αMβ2 integrin, thereby facilitating neutrophil infiltration into brain tissue and exacerbating brain injury.

Conclusions: Our results demonstrate that neutrophil CRACR2A promotes neutrophil recruitment to sites of sterile inflammation, such as ischemic stroke. Blocking the STIM1-CRACR2A interaction may be a novel therapeutic strategy to mitigate inflammation and consequent tissue injury.

Background: Declining cardiovascular mortality rates have been well-documented, yet temporal trends of sudden cardiac death (SCD) in young individuals remain unclear. We provide contemporary nationwide estimates of the temporal trends of SCD in young individuals (1-35 years of age) from 2000 through 2019 and correlate these trends to changes in out-of-hospital cardiac arrest (OHCA) patterns, rates of inherited cardiac diseases, and implantations of implantable cardioverter defibrillators (ICD).

Methods: All individuals between 1 and 35 years of age living in Denmark from 2000 through 2019 were included, with annual re-evaluation of the at-risk population in regard to age. Adjudication of SCD cases relied on multiple sources, including death certificates, medical files, and autopsy reports. Information on OHCA, diagnostic rates, and ICD implantations were captured from nationwide administrative registries. Annual incidence rates of SCD were calculated, and temporal trends in SCD incidence were computed as percentage change annualized. Trends in OHCA survival and characteristics, diagnostic rates of inherited cardiac diseases, and ICD implantations were assessed.

Results: During the 20-year study period (47.5 million person-years), 1057 SCDs were identified (median age, 29 years; 69% male). The overall incidence of SCD was 2.2 per 100 000 person-years and declined by 3.31% (95% CI, 2.42-4.20) annually, corresponding to a 49% (95% CI, 38.7-57.6) reduction during the study. Rates of witnessed SCD declined markedly (percentage change annualized -7.03% [95% CI, -8.57 to -5.48]), but we observed no changes in the rate of unwitnessed SCD (percentage change annualized -0.09% [95% CI, -1.48 to 1.31]). Therefore, the proportion of unwitnessed SCD increased by 79% (P<0.001). Survival after OHCA in young individuals (1 to 35 years of age) increased from 3.9% to 28%, mainly because of increased bystander cardiopulmonary resuscitation and defibrillation rates. Diagnostic rates of inherited cardiac diseases increased 10-fold (incidence rate ratio, 10.4 [95% CI, 8.46-12.90]) and the ICD implantation rate increased 2-fold (incidence rate ratio, 1.97 [95% CI, 1.51-2.60]).

Conclusions: SCD incidence rates in young individuals declined by 49% over the past 2 decades. The decline was paralleled by improved survival of OHCA, higher diagnostic rates of inherited cardiac diseases, and higher ICD implantation rates. However, rates of unwitnessed SCD were unchanged, which calls for new perspectives in preventive strategies.

Background: In the ARTESiA trial (Apixaban for the Reduction of Thromboembolism in Patients With Device-Detected Subclinical Atrial Fibrillation), apixaban, compared with aspirin, reduced stroke or systemic embolism in patients with device-detected subclinical atrial fibrillation (SCAF). Clinical guidelines recommend considering SCAF episode duration when deciding whether to prescribe oral anticoagulation for this population.

Methods: We performed a retrospective cohort study in ARTESiA. Using Cox regression adjusted for CHA₂DS₂-VASc score and treatment allocation (apixaban or aspirin), we assessed frequency of SCAF episodes and duration of the longest SCAF episode in the 6 months before randomization as predictors of stroke risk and of apixaban treatment effect.

Results: Among 3986 patients with complete baseline SCAF data, 703 (17.6%) had no SCAF episode ≥6 minutes in the 6 months before enrollment. Among 3283 patients (82.4%) with ≥1 episode of SCAF ≥6 minutes in the 6 months before enrollment, 2542 (77.4%) had up to 5 episodes, and 741 (22.6%) had ≥6 episodes. The longest episode lasted <1 hour in 1030 patients (31.4%), 1 to <6 hours in 1421 patients (43.3%), and >6 hours in 832 patients (25.3%). Higher baseline SCAF frequency was not associated with increased risk of stroke or systemic embolism: 1.1% for 1 to 5 episodes versus 1.2%/patient-year for ≥6 episodes (adjusted hazard ratio, 0.89 [95% CI, 0.59-1.34]). In an exploratory analysis, patients with previous SCAF but no episode ≥6 minutes in the 6 months before enrollment had a lower risk of stroke or systemic embolism than patients with at least one episode during that period (0.5% versus 1.1%/patient-year; adjusted hazard ratio, 0.48 [95% CI, 0.27-0.85]). The frequency of SCAF did not modify the reduction in stroke or systemic embolism with apixaban (P_interaction=0.1). The duration of the longest SCAF episode in the 6 months before enrollment was not associated with the risk of stroke or systemic embolism during follow-up (<1 hour: 1.0%/patient-year [reference]; 1-6 hours: 1.2%/patient-year [adjusted hazard ratio, 1.27 (95% CI, 0.85-1.90)]; >6 hours: 1.0%/patient-year [adjusted hazard ratio, 1.02 (95% CI, 0.63-1.66)]). SCAF duration did not modify the reduction in stroke or systemic embolism with apixaban (P_trend=0.1).

Conclusions: In ARTESiA, baseline SCAF frequency and longest episode duration were not associated with risk of stroke or systemic embolism and did not modify the effect of apixaban on reduction of stroke or systemic embolism.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01938248.

Background: GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose cotransporter 2) inhibitors both improve cardiovascular and kidney outcomes in people with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitors.

Methods: We searched MEDLINE and Embase databases from inception until July 12, 2024, for randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors, with findings supplemented by unpublished data. We estimated treatment effects by baseline SGLT2 inhibitor use using inverse variance-weighted meta-analysis. The main cardiovascular outcomes were major adverse cardiovascular events (nonfatal myocardial infarction, stroke, or cardiovascular death) and hospitalization for heart failure. Kidney outcomes included a composite of ≥50% reduction in estimated glomerular filtration rate, kidney failure or death caused by kidney failure, and annualized rate of decline in estimated glomerular filtration rate (estimated glomerular filtration rate slope). Serious adverse events and severe hypoglycemia were also evaluated. This meta-analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024565765).

Results: We identified 3 trials with 1743 of 17 072 (10.2%) participants with type 2 diabetes receiving an SGLT2 inhibitor at baseline. GLP-1 receptor agonists reduced the risk of major adverse cardiovascular events by 21% (hazard ratio [HR], 0.79 [95% CI, 0.71-0.87]), with consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR, 0.77 [95% CI, 0.54-1.09] and HR, 0.79 [95% CI, 0.71-0.87], respectively; P-heterogeneity=0.78). The effect on hospitalization for heart failure was similarly consistent regardless of SGLT2 inhibitor use (HR, 0.58 [95% CI, 0.36-0.93] and HR, 0.73 [95% CI, 0.63-0.85]; P-heterogeneity=0.26). Effects on the composite kidney outcome (risk ratio, 0.79 [95% CI, 0.66-0.95]) and estimated glomerular filtration rate slope (0.78 mL/min/1.73 m²/y [95% CI, 0.57-0.98]) also did not vary according to SGLT2 inhibitor use (P-heterogeneity=0.53 and 0.94, respectively). Serious adverse effects and severe hypoglycemia were also similar regardless of SGLT2 inhibitor use (P-heterogeneity=0.29 and 0.50, respectively).

Conclusions: In people with type 2 diabetes, the cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use.