Beyond antithrombotics: recent advances in pharmacological risk factor management for secondary stroke prevention.

Patients with ischaemic stroke represent a diverse group with several cardiovascular risk factors and comorbidities, which classify them as patients at very high risk of stroke recurrence, cardiovascular adverse events or death. In addition to antithrombotic therapy, which is important for secondary stroke prevention in most patients with stroke, cardiovascular risk factor assessment and treatment also contribute significantly to the reduction of mortality and morbidity. Dyslipidaemia, diabetes mellitus and hypertension represent common and important modifiable cardiovascular risk factors among patients with stroke, while early recognition and treatment may have a significant impact on patients' future risk of major cardiovascular events. In recent years, there have been numerous advancements in pharmacological agents aimed at secondary cardiovascular prevention. These innovations, combined with enhanced awareness and interventions targeting adherence and persistence to treatment, as well as lifestyle modifications, have the potential to substantially alleviate the burden of cardiovascular disease, particularly in patients who have experienced ischaemic strokes. This review summarises the evidence on the contemporary advances on pharmacological treatment and future perspectives of secondary stroke prevention beyond antithrombotic treatment.

Prevalence and Factors Associated with Carotid Stenosis in Acute Ischemic Stroke Patients with Atrial Fibrillation.

INTRODUCTION: Among stroke patients with atrial fibrillation (AF), it is not uncommon to identify carotid atherosclerosis. This study aimed to estimate the prevalence of, and factors associated with, carotid atherosclerosis among patients with AF and acute ischemic stroke. PATIENTS AND METHODS: Prospectively collected data from consecutive patients with anterior ischemic stroke and AF who underwent carotid imaging from 10 stroke registries were categorized retrospectively according to the degree of stenosis in: no atherosclerosis, stenosis <50%, stenosis ≥50%, and occlusion. Logistic regression analysis was used to identify factors associated with ipsilateral carotid atherosclerosis. RESULTS: Among 2,955 patients with ischemic stroke and AF, carotid atherosclerosis was evident in 1,022 (34.6%) patients, while carotid stenosis ≥50% and occlusion were identified in 204 (6.9%) and 168 (5.7%) patients, respectively. Ipsilateral carotid stenosis ≥50% or occlusion was associated with higher age (OR: 1.15, 95% CI: 1.01-1.32, per decade), previous ischemic stroke or transient ischemic attack (OR: 1.70, 95% CI: 1.29-2.25), peripheral artery disease (OR: 1.85, 95% CI: 1.23-2.78), coronary artery disease (OR: 1.53, 95% CI: 1.16-2.04), and statin treatment on admission (OR: 1.30, 95% CI: 1.01-1.67). Patients with lacunar stroke had a lower likelihood of stenosis ≥50% or occlusion (OR: 0.29, 95% CI: 0.13-0.68). Compared to the absence of atherosclerotic disease, atherosclerosis in one and two arterial beds was associated with the identification of ipsilateral carotid stenosis (OR: 1.49, 95% CI: 1.22-2.98 and OR: 3.18, 95% CI: 1.85-5.49, respectively). CONCLUSION: Among acute ischemic stroke patients with AF, 1 out of 3 had ipsilateral carotid atherosclerosis, and 1 out of 8 had ipsilateral carotid stenosis ≥50% or occlusion. Atherosclerosis in two arterial beds was the most important predictor for the identification of ipsilateral carotid stenosis. Among ischemic stroke patients with AF, carotid atherosclerosis is common, while carotid imaging should not be overlooked, especially in those with coronary or/and peripheral artery disease.

Reperfusion therapies in patients with acute ischaemic stroke and atrial fibrillation: data on safety and effectiveness from a multi-centre cohort study.

BACKGROUND: Intravenous thrombolysis (IVT) and/or endovascular therapy (EVT) are currently considered best practices in acute stroke patients. Data regarding the efficacy and safety of reperfusion therapies in patients with atrial fibrillation (AF) are conflicting as regards haemorrhagic transformation, mortality, and functional outcome. This study sought to investigate for any differences, in terms of safety and effectiveness, between AF patients with acute ischaemic stroke (AIS) treated and untreated with reperfusion therapies. METHODS: Data from two multicenter cohort studies (RAF and RAF-NOACs) on consecutive patients with AF and AIS were analyzed to compare patients treated and not treated with reperfusion therapies (IVT and/or EVT). Multivariable logistic regression analysis was performed to identify independent predictors for outcome events: 90-day good functional outcome and mortality. A propensity score matching (PSM) analysis compared treated and untreated patients. RESULTS: Overall, 441 (25.4%) were included in the reperfusion-treated group and 1,295 (74.6%) in the untreated group. The multivariable model suggested that reperfusion therapies were significantly associated with good functional outcome. Rates of mortality and disability were higher in patients not treated, especially in the case of higher NIHSS scores. In the PSM comparison, 173/250 patients (69.2%) who had received reperfusion therapies had good functional outcome at 90 days, compared to 146/250 (58.4%) untreated patients (p = 0.009, OR: 1.60, 95% CI:1.11-2.31). CONCLUSIONS: Patients with AF and AIS treated with reperfusion therapies had a significantly higher rate of good functional outcome and lower rates of mortality compared to those patients with AF and AIS who had undergone conservative treatment.

Risk of myocardial infarction and ischemic stroke in individuals with first-diagnosed paroxysmal vs. non-paroxysmal atrial fibrillation under anticoagulation.

AIMS: There is conflicting evidence on whether the type of atrial fibrillation (AF) is associated with risk of cardiovascular events, including acute myocardial infarction (MI) and ischemic stroke. The aim of the present study was to investigate whether the risk of MI and ischemic stroke differs between individuals with first-diagnosed paroxysmal vs. non-paroxysmal AF treated with anticoagulants. METHODS AND RESULTS: De-identified electronic medical records from the TriNetX federated research network were used. Individuals with a new diagnosis of paroxysmal AF who had no evidence of other types of AF in their records were 1:1 propensity score-matched with individuals with non-paroxysmal AF, defined as persistent or chronic AF, who had no evidence of other types of AF in their records. All patients were followed for three years for the outcomes of MI and ischemic stroke. Cox proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). In the propensity-matched cohort, among 24 848 well-matched AF individuals [mean age 74.4 ± 10.4; 10 101 (40.6%) female], 410 (1.7%) were diagnosed with acute MI and 875 (3.5%) with ischemic stroke during the three-year follow-up. Individuals with paroxysmal AF had significantly higher risk of acute MI (HR: 1.65, 95%CI: 1.35-2.01) compared to those with non-paroxysmal AF. First diagnosed paroxysmal AF was associated with higher risk of non-ST elevation MI (nSTEMI) (HR: 1.89, 95%CI: 1.44-2.46). No significant association was observed between the type of AF and risk of ischemic stroke (HR: 1.09, 95%CI: 0.95-1.25). CONCLUSION: Patients with first-diagnosed paroxysmal AF had higher risk of acute MI compared to individuals with non-paroxysmal AF, attributed to the higher risk of nSTEMI among patients with first-diagnosed paroxysmal AF. There was no significant association between type of AF and risk of ischemic stroke.

Stroke in Atrial Fibrillation and Other Atrial Dysrhythmias.

PURPOSE OF REVIEW: Atrial fibrillation (AF) is a major risk factor for systemic embolism and ischaemic stroke. Furthermore, AF-related strokes are associated with higher mortality, greater disability, longer hospital stays and lower rates of hospital discharge than strokes caused by other reasons. The aim of this review to summarise the existing evidence on the association of AF with ischemic stroke and provide insights on the pathophysiological mechanisms and the clinical management of patients with AF in order to reduce the burden of ischemic stroke. RECENT FINDINGS: Beyond Virchow's triad, several pathophysiological mechanisms associated with structural changes in the left atrium, which may precede the identification of AF, may contribute to the increased risk of arterial embolism in AF patients. Individualised thromboembolic risk stratification based on CHA2DS2-VASc score and clinically relevant biomarkers provides essential tool towards a personalised holistic approach in thromboembolism prevention. Anticoagulation remains the cornerstone of stroke prevention moving from vitamin K antagonists (VKA) to safer non-vitamin K direct oral anticoagulants in the majority of AF patients. Despite the efficacy and safety of oral anticoagulation, still the equilibrium between thrombosis and haemostasis in AF patients remains suboptimal and future directions in anticoagulation and cardiac intervention may provide novel treatment options in stroke prevention. This review summarises the pathophysiologic mechanisms of thromboembolism, aiming the current and potential future perspectives in stroke prevention in AF patients.

Incidence of Stroke in Randomized Trials of COVID-19 Therapeutics: A Systematic Review and Meta-Analysis.

BACKGROUND: COVID-19 has been frequently associated with an increased risk of thrombotic complications. There have also been reports of an increased likelihood of stroke, although its true incidence in patients with COVID-19 is currently unknown. METHODS: Electronic databases PubMed and Scopus were searched from inception up to July 30, 2021 to identify randomized controlled studies in patients with confirmed COVID-19 undergoing one or more interventions. Studies were screened for eligibility using a predefined inclusion criterion and selected using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A random-effects model meta-analysis was conducted, and heterogeneity was assessed using I-squared test. RESULTS: Out of 3960 potentially eligible articles, 77 randomized studies (38 732 patients) were included. Mean age of the study population was 55±9.3 years. Females constituted 38% of the study population and mean duration of follow-up after study enrollment was 23±12.9 days. Cumulative incidence of stroke in the overall study population was 0.001 (95% CI, 0.001-0.002) with a total of 65 events in 38 732 patients, corresponding to an absolute incidence of 0.168%. Incidence of stroke in the inpatient population was 0.001 (95% CI, 0.001-0.002; 65 events in 37 069 patients), corresponding to an absolute incidence of 0.175%. No strokes were observed in the outpatient setting. CONCLUSIONS: The overall incidence of stroke in patients with COVID-19 appears to be lower than that reported in previous observational reports.

Lipids and atrial fibrillation: New insights into a paradox.

In this Perspective, Dimitrios Sagris, Stephanie Harrison, and Gregory Lip discuss new evidence concerning the paradoxical relationship between circulating lipids and atrial fibrillation.

COVID-19 and ischemic stroke.

Since the onset of the COVID-19 pandemic, a substantial proportion of COVID-19 patients had documented thrombotic complications and ischemic stroke. Several mechanisms related to immune-mediated thrombosis, the renin angiotensin system and the effect of SARS-CoV-2 in cardiac and brain tissue may contribute to the pathogenesis of ischemic stroke in patients with COVID-19. Simultaneously, significant strains on global healthcare delivery, including ischemic stroke management, have made treatment of stroke in the setting of COVID-19 particularly challenging. In this review, we summarize the current knowledge on epidemiology, clinical manifestation, and pathophysiology of ischemic stroke in patients with COVID-19 to bridge the gap from bench to bedside and clinical practice during the most challenging global health crisis of the last decades.

Machine-Learning-Derived Model for the Stratification of Cardiovascular risk in Patients with Ischemic Stroke.

Background Stratification of cardiovascular risk in patients with ischemic stroke is important as it may inform management strategies. We aimed to develop a machine-learning-derived prognostic model for the prediction of cardiovascular risk in ischemic stroke patients. MATERIALS AND METHODS: Two prospective stroke registries with consecutive acute ischemic stroke patients were used as training/validation and test datasets. The outcome assessed was major adverse cardiovascular event, defined as non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death during 2-year follow-up. The variables selection was performed with the LASSO technique. The algorithms XGBoost (Extreme Gradient Boosting), Random Forest and Support Vector Machines were selected according to their performance. The evaluation of the classifier was performed by bootstrapping the dataset 1000 times and performing cross-validation by splitting in 60% for the training samples and 40% for the validation samples. RESULTS: The model included age, gender, atrial fibrillation, heart failure, peripheral artery disease, arterial hypertension, statin treatment before stroke onset, prior anticoagulant treatment (in case of atrial fibrillation), creatinine, cervical artery stenosis, anticoagulant treatment at discharge (in case of atrial fibrillation), and statin treatment at discharge. The best accuracy was measured by the XGBoost classifier. In the validation dataset, the area under the curve was 0.648 (95%CI:0.619-0.675) and the balanced accuracy was 0.58 ± 0.14. In the test dataset, the corresponding values were 0.59 and 0.576. CONCLUSIONS: We propose an externally validated machine-learning-derived model which includes readily available parameters and can be used for the estimation of cardiovascular risk in ischemic stroke patients.

Carotid Atherosclerosis and Patent Foramen Ovale in Embolic Stroke of Undetermined Source.

BACKGROUND: Carotid atherosclerosis and likely pathogenic patent foramen ovale (PFO) are two potential embolic sources in patients with embolic stroke of undetermined source (ESUS). The relationship between these two mechanisms among ESUS patients remains unclear. AIM: To investigate the relation between carotid atherosclerosis and likely pathogenic PFO in patients with ESUS. We hypothesized that ipsilateral carotid atherosclerotic plaques are less prevalent in ESUS with likely pathogenic PFO compared to patients with likely incidental PFO or without PFO. METHODS: The presence of PFO was assessed with transthoracic echocardiography with microbubble test and, when deemed necessary, through trans-oesophageal echocardiography. The presence of PFO was considered as likely incidental if the RoPE (Risk of Paradoxical Embolism) score was 0-6 and likely pathogenic if 7-10. RESULTS: Among 374 ESUS patients (median age: 61years, 40.4% women), there were 63 (49.6%) with likely incidental PFO, 64 (50.4%) with likely pathogenic PFO and 165 (44.1%) with ipsilateral carotid atherosclerosis. The prevalence of ipsilateral carotid atherosclerosis was lower in patients with likely pathogenic PFO (7.8%) compared to patients with likely incidental PFO (46.0%) or patients without PFO (53.0%) (p<0.001). After adjustment for multiple confounders, the prevalence of ipsilateral carotid atherosclerosis remained lower in patients with likely pathogenic PFO compared to patients with likely incidental PFO or without PFO (adjusted OR=0.32, 95%CI:0.104-0.994, p=0.049). CONCLUSIONS: The presence of carotid atherosclerosis is inversely related to the presence of likely pathogenic PFO in patients with ESUS.

Antithrombotic Treatment in Cryptogenic Stroke Patients With Patent Foramen Ovale: Systematic Review and Meta-Analysis.

Background and Purpose- It is unclear whether treatment with anticoagulants or antiplatelets is the optimal strategy in patients with stroke or transient ischemic attack of undetermined cause and patent foramen ovale that is not percutaneously closed. We aimed to perform a systematic review and meta-analysis of randomized controlled trials to compare anticoagulant or antiplatelet treatment in this population. Methods- We searched PubMed until July 16, 2019 for trials comparing anticoagulants and antiplatelet treatment in patients with stroke/transient ischemic attack and medically treated patent foramen ovale using the terms: "cryptogenic or embolic stroke of undetermined source" and "stroke or cerebrovascular accident or transient ischemic attack" and "patent foramen ovale or patent foramen ovale or paradoxical embolism" and "trial or study" and "antithrombotic or anticoagulant or antiplatelet." The outcomes assessed were stroke recurrence, major bleeding, and the composite end point of stroke recurrence or major bleeding. We used 3 random-effects models: (1) a reference model based on the inverse variance method with the Sidik and Jonkman heterogeneity estimator; (2) a strict model, implementing the Hartung and Knapp method; and (3) a commonly used Bayesian model with a prior that assumes moderate to large between-study variance. Results- Among 112 articles identified in the literature search, 5 randomized controlled trials were included in the meta-analysis (1720 patients, mean follow-up 2.3±0.5 years). Stroke recurrence occurred at a rate of 1.73 per 100 patient-years in anticoagulant-assigned patients and 2.39 in antiplatelet-assigned patients (hazard ratio, 0.68; 95% CI, 0.32-1.48 for the Sidik and Jonkman estimator). Major bleeding occurred at a rate of 1.16 per 100 patient-years in anticoagulant-assigned patients and 0.68 in antiplatelet-assigned patients (hazard ratio, 1.61; 95% CI, 0.72-3.59 for the Sidik and Jonkman estimator). The composite outcome occurred in 52 anticoagulant-assigned and 54 antiplatelet-assigned patients (odds ratio, 1.05; 95% CI, 0.65-1.70 for the Sidik and Jonkman estimator). Conclusions- We cannot exclude a large reduction of stroke recurrence in anticoagulant-assigned patients compared with antiplatelet-assigned, without significant differences in major bleeding. An adequately powered randomized controlled trial of a non-vitamin K antagonist versus aspirin is warranted.

Closure of Patent Foramen Ovale Versus Medical Therapy in Patients With Cryptogenic Stroke or Transient Ischemic Attack: Updated Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Previous systematic reviews and meta-analyses compared the efficacy and safety of patent foramen ovale (PFO) closure versus medical treatment in patients with cryptogenic stroke or transient ischemic attack (TIA). Recently, new evidence from randomized trials became available. METHODS: We searched PubMed until September 24, 2017, for trials comparing PFO closure with medical treatment in patients with cryptogenic stroke/TIA using the items: stroke or cerebrovascular accident or TIA and patent foramen ovale or paradoxical embolism and trial or study. RESULTS: Among 851 identified articles, 5 were eligible. In 3627 patients with 3.7-year mean follow-up, there was significant difference in ischemic stroke recurrence (0.53 versus 1.1 per 100 patient-years, respectively; odds ratio [OR], 0.43; 95% confidence intervals (CI), 0.21-0.90; relative risk reduction, 50.5%; absolute risk reduction, 2.11%; and number needed to treat to prevent 1 event, 46.5 for 3.7 years). There was no significant difference in TIAs (0.78 versus 0.98 per 100 patient-years, respectively; OR, 0.80; 95% CI, 0.53-1.19) and all-cause mortality (0.18 versus 0.23 per 100 patient-years, respectively; OR, 0.73; 95% CI, 0.34-1.56). New-onset atrial fibrillation occurred more frequently in the PFO closure arm (1.3 versus 0.25 per 100 patient-years, respectively; OR, 5.15; 95% CI, 2.18-12.15) and resolved in 72% of cases within 45 days, whereas rates of myocardial infarction (0.12 versus 0.09 per 100 patient-years, respectively; OR, 1.22; 95% CI, 0.25-5.91) and any serious adverse events (7.3 versus 7.3 per 100 patient-years, respectively; OR, 1.07; 95% CI, 0.92-1.25) were similar. CONCLUSIONS: In patients with cryptogenic stroke/TIA and PFO who have their PFO closed, ischemic stroke recurrence is less frequent compared with patients receiving medical treatment. Atrial fibrillation is more frequent but mostly transient. There is no difference in TIA, all-cause mortality, or myocardial infarction.

MgcRacGAP, a cytoskeleton regulator, inhibits HIF-1 transcriptional activity by blocking its dimerization.

Hypoxia inducible factor-1 (HIF-1), a dimeric transcription factor of the bHLH-PAS family, is comprised of HIF-1α, which is inducible by hypoxia and ARNT or HIF-1ß, which is constitutively expressed. HIF-1 is involved in cellular homeostasis under hypoxia, in development and in several diseases affected by oxygen availability, particularly cancer. Since its expression is positively correlated with poor outcome prognosis for cancer patients, HIF-1 is a target for pharmaceutical therapy. We have previously shown that male germ cell Rac GTPase activating protein (MgcRacGAP), a regulator of Rho proteins which are principally involved in cytoskeletal organization, binds to HIF-1α and inhibits its transcriptional activity. In this work, we have explored the mechanism of the MgcRacGAP-mediated HIF-1 inactivation. We show that the Myo domain of MgcRacGAP, which is both necessary and sufficient for HIF-1 repression, binds to the PAS-B domain of HIF-1α. Furthermore MgcRacGAP competes with ARNT for binding to the HIF-1α PAS-B domain, as shown by in vitro binding pull down assays. In mammalian cells, ARNT overexpression can overcome the MgcRacGAP-mediated inhibition and MgcRacGAP binding to HIF-1α in vivo inhibits its dimerization with ARNT. We additionally present results indicating that MgcRacGAP binding to HIF-1α is specific, since it does not affect the transcriptional activity of HIF-2, a close evolutionary relative of HIF-1 also involved in hypoxia regulation and cancer. Our results reveal a new mechanism for HIF-1 transcriptional activity regulation, suggest a novel hypoxia-cytoskeleton link and provide new tools for selective HIF-1 inhibition.

Adherence to an integrated care pathway for stroke is associated with lower risk of major cardiovascular events: A report from the Athens Stroke Registry.

BACKGROUND: A recent European Society of Cardiology (ESC) Council on Stroke position paper proposed a holistic integrated care management approach for stroke patients, to improve cardiovascular outcomes. The impact of implementing the ABCstroke pathway 'concept' on clinical outcomes has never been estimated before. In order to investigate the potential effect of ABCstroke pathway adherence to cardiovascular outcomes post stroke, we performed a post-hoc analysis from the Athens Stroke Registry. METHODS AND RESULTS: This analysis was performed in the Athens Stroke Registry, which includes all consecutive patients with acute first-ever ischemic stroke. The Kaplan-Meier product limit was used to estimate the cumulative hazard of each outcome according to adherence with the ABCstroke pathway. We studied 2513 patients [median (IQR) age 71 (62-78) years; 37.7 % female] with ischemic stroke with median follow-up period of 30 (6-75) months. Full adherence to the ABC pathway was identified in 156 (6.2 %) of the patients, while 192 (7.6 %) did not adhere to any of the therapeutic pillars of ABCstroke. Full adherence to ABC treatment pathway was associated with significant reduction of stroke recurrence, compared to patients with no or partial adherence (aHR: 0.61; 95 %CI: 0.37-0.99), as well as a lower risk of MACE (HR: 0.59; 0.39-0.88) and death (aHR: 0.22; 95 %CI: 0.12-0.41). CONCLUSION: Full adherence to the ABCstroke pathway based on the current guidelines was evident in only 6.2 % of our ischaemic stroke cohort but was independently associated with lower risks of stroke recurrence, major cardiovascular events and mortality. This highlights a potential opportunity to improve clinical outcomes post-stroke with a holistic or integrated care management approach.

Direct oral anticoagulants are associated with lower risk of dementia in patients with atrial fibrillation.

BACKGROUND AND AIM: Atrial fibrillation (AF) is associated with increased risk of dementia. Whether direct oral anticoagulation (DOAC) reduce this risk compared to vitamin-K antagonist (VKA) is unclear. The aim of this study was to assess the risk of new all-cause dementia and vascular dementia in AF patients, treated with either DOAC or VKAs. METHODS: Anonymized electronic medical records from the TriNetX federated research network were used. AF patients treated with DOACs within 1 month of AF diagnosis, were 1:1 propensity score-matched with those treated with a VKA. The analysis included patients who completed 5 and 10 years of follow-up and were assessed for all-cause dementia and vascular dementia. Cox proportional hazard models were used to hazard ratios (HR), respectively with 95% confidence intervals (CIs). RESULTS: Among patients who completed 5 years of follow-up, after propensity score matching the final cohort consisted of 215,404 well-matched AF patients. All-cause dementia was diagnosed in 4,153 (3.9%) patients among those treated with DOACs and 4,150 (3.9%) among the VKA-treated patients (HR: 1.01, 95%CI: 0.96-1.05). Among patients 65-74 years old who were followed, DOAC treatment was associated with lower risk of dementia compared to VKAs (HR: 0.72; 95%CI: 0.59-0.86). Among patients who completed 10 years of follow-up, after propensity score matching the final cohort consisted of 19,208 well-matched AF patients. All-cause dementia was diagnosed in 314 (3.3%) patients among those treated with DOACs and 451 (4.7%) among the VKA-treated patients. DOAC treatment was associated with significantly lower risk of all-cause dementia during a follow-up period of 10 years compared to VKA treatment (HR: 0.72, 95%CI: 0.62-0.83), which remained consistent in patiens ≥65 years old. CONCLUSION: This propensity-score matched analysis showed that among AF patients, treatment with a DOACs for a period of 10 years was associated with lower risk of all-cause dementia and vascular dementia compared to VKA treatment, an effect which was not apparent in those treated for shorter duration. This finding requires confirmation in ongoing randomised controlled trials.

Sodium-glucose cotransporter-2 inhibitors in heart failure patients across the range of body mass index: a systematic review and meta-analysis of randomized controlled trials.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in patients with heart failure, with or without diabetes. We sought to assess whether there is an interaction of these effects with body mass index (BMI). A systematic review of the MEDLINE and Scopus databases (last search: November 15th, 2022) was performed according to the PRISMA statement. Studies eligible for this review were randomized control trials (RCTs) with patients with chronic heart failure with either preserved or reduced ejection fraction randomly assigned to SGLT2 inhibitors or placebo. Data were extracted independently by two reviewers. BMI was classified according to the WHO classification into under/normal weight (BMI: < 25 kg/m2), overweight (BMI: 25-29.9 kg/m2), obesity class I (BMI: 30-34.9 kg/m2), and obesity classes II/III (BMI: ≥ 35 kg/m2). All analyses were performed using RevMan 5.4. Among 1461 studies identified in the literature search, 3 were eligible and included in the meta-analysis. Among 14,737 patients (32.2% were women), 7,367 were randomized to an SGLT2 inhibitor (dapagliflozin or empagliflozin) and 7,370 to placebo. There were significantly fewer hospitalizations for HF (OR: 0.70, 95%CI: 0.64-0.76), cardiovascular deaths (OR:0.86, 95%CI: 0.77-0.97) and all-cause deaths (OR:0.90, 95%CI: 0.82-0.98) in the SGLT2 inhibitors group compared to the placebo group, without any interaction with BMI group (test for subgroup differences: x2 = 1.79, p = 0.62; x2 = 0.27, p = 0.97; x2 = 0.39, p = 0.94, respectively). There is no interaction between the efficacy of SGLT2 inhibitors and BMI in patients with HF with either preserved or reduced ejection fraction. SGLT2 inhibitors are associated with improved outcomes regardless of the BMI.Trial registration: PROSPERO ID: CRD42022383643.

Biomedical Composites of Polycaprolactone/Hydroxyapatite for Bioplotting: Comprehensive Interpretation of the Reinforcement Course.

Robust materials in medical applications are sought after and researched, especially for 3D printing in bone tissue engineering. Poly[ε-caprolactone] (PCL) is a commonly used polymer for scaffolding and other medical uses. Its strength is a drawback compared to other polymers. Herein, PCL was mixed with hydroxyapatite (HAp). Composites were developed at various concentrations (0.0-8.0 wt. %, 2.0 step), aiming to enhance the strength of PCL with a biocompatible additive in bioplotting. Initially, pellets were derived from the shredding of filaments extruded after mixing PCL and HAp at predetermined quantities for each composite. Specimens were then manufactured by bioplotting 3D printing. The samples were tested for their thermal and rheological properties and were also mechanically, morphologically, and chemically examined. The mechanical properties included tensile and flexural investigations, while morphological and chemical examinations were carried out employing scanning electron microscopy and energy dispersive spectroscopy, respectively. The structure of the manufactured specimens was analyzed using micro-computed tomography with regard to both their dimensional deviations and voids. PCL/HAp 6.0 wt. % was the composite that showed the most enhanced mechanical (14.6% strength improvement) and structural properties, proving the efficiency of HAp as a reinforcement filler in medical applications.