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Background and Purpose: Guidelines help physicians to provide optimal care for stroke patients, but implementation is challenging due to the quantity of recommendations. Therefore a practical overview related to applicability of recommendations can be of assistance., Methods: A systematic review was performed on ischaemic stroke guidelines published in scientific journals, covering the whole acute care process for patients with ischaemic stroke. After data extraction, experts rated the recommendations on dimensions of applicability, that is, actionability, feasibility and validity, on a 9-point Likert scale. Agreement was defined as a score of ≥8 by ≥80% of the experts., Results: Eighteen articles were identified and 48 recommendations were ultimately extracted. Papers were included only if they described the whole acute care process for patients with ischaemic stroke. Data extraction and analysis revealed variation in terms of both content and comprehensiveness of this description. Experts reached agreement on 34 of 48 (70.8%) recommendations in the dimension actionability, for 16 (33.3%) in feasibility and for 15 (31.3%) in validity. Agreement on all three dimensions was reached for seven (14.6%) recommendations: use of a stroke unit, exclusion of intracerebral haemorrhage as differential diagnosis, administration of intravenous thrombolysis, performance of electrocardiography/cardiac evaluation, non-invasive vascular examination, deep venous thrombosis prophylaxis and administration of statins if needed., Discussion and Conclusion: Substantial variation in agreement was revealed on the three dimensions of the applicability of recommendations. This overview can guide stroke physicians in improving the care process and removing barriers where implementation may be hampered by validity and feasibility., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of antipsychotic drugs (both first- and second-generation antipsychotics) compared to placebo on body weight gain, psychological symptoms, acceptability, and adverse events for people with anorexia nervosa., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Aims: Burst steroid therapy, effective in acute respiratory diseases, may benefit patients with acute heart failure (AHF) in whom inflammatory activation is associated with adverse outcomes., Methods and Results: CORTAHF assessed whether burst steroid therapy reduces inflammation and results in better quality of life and clinical outcomes in AHF. Patients with AHF, N-terminal pro-B-type natriuretic peptide >1500 pg/ml, and high-sensitivity C-reactive protein (hsCRP) >20 mg/L were randomized 1:1 to oral, once daily 40 mg prednisone for 7 days or usual care, without blinding. Patients were followed for 90 days. A total of 101 patients were randomized. At day 7 the primary endpoint, hsCRP decreased in both arms - adjusted geometric mean ratios (GMRs) were 0.30 and 0.40 in the prednisone and usual care arms (ratio of GMRs 0.75, 95% confidence interval [CI] 0.56-1.00, p = 0.0498). The 90-day risk of worsening heart failure (HF), HF readmission or death as reported by the unblinded investigators was significantly lower in the prednisone group (10.4%) than in usual care (30.8%) (hazard ratio 0.31, 95% CI 0.11-0.86, p = 0.016). The EQ-5D visual analogue scale score as reported by the unblinded patients increased more in the prednisone group on day 7 (least squares mean difference 2.57, 95% CI 0.12-5.01 points, p = 0.040). All effects were statistically significant in the pre-specified subgroup with centrally-measured interleukin-6 >13 pg/ml. Adverse events, particularly hyperglycaemia, occurred more in the prednisone group with no difference in infection rate., Conclusion: In this small open-label study of patients with AHF, burst steroid therapy was associated with reduced inflammation as measured by hsCRP levels at day 7 (primary endpoint). Secondary endpoints showed improved quality of life at day 7 and reduced 90-day risk of death or worsening HF. Large prospective studies are needed to evaluate these findings., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus., (© 2024 European Society of Cardiology.)

Background and Purpose: Cervical artery dissection (CAD) represents a leading cause of unilateral lower cranial nerve IX-XII palsy, known as Collet-Sicard syndrome (CSS). High-resolution magnetic resonance imaging (HR-MRI) is widely used in the evaluation of patients with CAD, providing information regarding vessel wall abnormalities and intraluminal thrombus., Methods: We present a patient with palsy of multiple lower cranial nerves in the context of CSS, attributed to unilateral spontaneous internal carotid artery dissection., Results: We describe a 68-year-old man with unremarkable previous history, who presented with subacute, gradually worsening dysphagia and hoarse voice. Clinical examination revealed right-sided palsy of cranial nerves IX-XII. Three-dimensional fat-saturated black-blood T1-weighted high-resolution vessel wall imaging disclosed spontaneous dissection with intramural hematoma along the distal right internal carotid artery. Neck MRI showed inward displacement of right aryepiglottic fold, right pyriform sinus dilatation, and right true vocal cord in middle position, indicative of right vagus nerve palsy, atrophy of right trapezius and sternocleidomastoid muscles, due to right spinal accessory nerve palsy, and unilateral tongue atrophy with fatty infiltration, characteristic for right hypoglossal nerve palsy., Conclusions: This case highlights the utility of high-resolution vessel wall imaging and especially fat-saturated T1-weighted black-blood SPACE (sampling perfection with application-optimized contrast using different flip-angle evolutions) sequences in the accurate diagnosis of CAD, revealing the characteristic mural hematoma and intimal flap. HR-MRI is also valuable in the recognition of indirect signs of lower cranial nerve compression., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Patient-reported outcome measures (PROMs) are used to assess a patient's health status at a particular point in time. They are essential in the development of person-centred care. This paper reviews studies performed on PROMs for assessing AR and asthma control, in particular VAS scales that are included in the app MASK-air ® (Mobile Airways Sentinel networK) for asthma and rhinitis. VASs were initially developed on paper and pencil and tested for their criterion validity, cut-offs and responsiveness. Then, a multicentric, multinational, double-blind, placebo-controlled, randomised control trial (DB-PC-RCT) using an electronic VAS form was carried out. Finally, with the development of MASK-air ® in 2015, previously validated VAS questions were adapted to the digital format and further methodologic evaluations were performed. VAS for asthma, rhinitis, conjunctivitis, work and EQ-5D are included in the app. Additionally, two control-medication scores for allergic symptoms of asthma (e-DASTHMA) were validated for their criterion validity, cut-offs and responsiveness., (© 2024 The Author(s). Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Aim: The RESHAPE-HF2 trial is designed to assess the efficacy and safety of the MitraClip device system for the treatment of clinically important functional mitral regurgitation (FMR) in patients with heart failure (HF). This report describes the baseline characteristics of patients enrolled in the RESHAPE-HF2 trial compared to those enrolled in the COAPT and MITRA-FR trials., Methods and Results: The RESHAPE-HF2 study is an investigator-initiated, prospective, randomized, multicentre trial including patients with symptomatic HF, a left ventricular ejection fraction (LVEF) between 20% and 50% with moderate-to-severe or severe FMR, for whom isolated mitral valve surgery was not recommended. Patients were randomized 1:1 to a strategy of delivering or withholding MitraClip. Of 506 patients randomized, the mean age of the patients was 70 ± 10 years, and 99 of them (20%) were women. The median EuroSCORE II was 5.3 (2.8-9.0) and median plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 2745 (1407-5385) pg/ml. Most patients were prescribed beta-blockers (96%), diuretics (96%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (82%) and mineralocorticoid receptor antagonists (82%). The use of sodium-glucose cotransporter 2 inhibitors was rare (7%). Cardiac resynchronization therapy (CRT) devices had been previously implanted in 29% of patients. Mean LVEF, left ventricular end-diastolic volume and effective regurgitant orifice area (EROA) were 31 ± 8%, 211 ± 76 ml and 0.25 ± 0.08 cm 2 , respectively, whereas 44% of patients had mitral regurgitation severity of grade 4+. Compared to patients enrolled in COAPT and MITRA-FR, those enrolled in RESHAPE-HF2 were less likely to have mitral regurgitation grade 4+ and, on average, HAD lower EROA, and plasma NT-proBNP and higher estimated glomerular filtration rate, but otherwise had similar age, comorbidities, CRT therapy and LVEF., Conclusion: Patients enrolled in RESHAPE-HF2 represent a third distinct population where MitraClip was tested in, that is one mainly comprising of patients with moderate-to-severe FMR instead of only severe FMR, as enrolled in the COAPT and MITRA-FR trials. The results of RESHAPE-HF2 will provide crucial insights regarding broader application of the transcatheter edge-to-edge repair procedure in clinical practice., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Biologically active adrenomedullin (bio-ADM) is a promising marker of residual congestion. The STRONG-HF trial showed that high-intensity care (HIC) of guideline-directed medical therapy (GDMT) improved congestion and clinical outcomes in heart failure (HF) patients. The association between bio-ADM, decongestion, outcomes and the effect size of HIC of GDMT remains to be elucidated., Methods and Results: We measured plasma bio-ADM concentrations in 1005 patients within 2 days prior to anticipated discharge (baseline) and 90 days later. Bio-ADM correlated with most signs of congestion, with the exception of rales. Changes in bio-ADM were strongly correlated with change in congestion status from baseline to day 90 (gamma -0.24; p = 0.0001). Patients in the highest tertile of baseline bio-ADM concentrations were at greater risk than patients in the lowest tertile for the primary outcome of 180-day all-cause mortality or HF rehospitalization (hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.42-3.22) and 180-day HF rehospitalization (HR 2.33, 95% CI 1.38-3.94). Areas under the receiver-operating characteristic curves were 0.5977 (95% CI 0.5561-0.6393), 0.5800 (95% CI 0.5356-0.6243), and 0.6159 (95% CI 0.5711-0.6607) for bio-ADM, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their combination, respectively, suggesting that both bio-ADM and NT-proBNP provided similarly modest discrimination for this outcome. A trend towards better discrimination by combined bio-ADM and NT-proBNP than NT-proBNP alone was found (p = 0.059). HIC improved the primary outcome, irrespective of baseline bio-ADM concentration (interaction p = 0.37). In contrast to NT-proBNP, the 90-day change in bio-ADM did not differ significantly between HIC and usual care., Conclusions: Bio-ADM is a marker of congestion and predicts congestion at 3 months after a HF hospitalization. Higher bio-ADM was modestly associated with a higher risk of death and early hospital readmission and may have added value when combined with NT-proBNP., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and Purpose: Transcranial Doppler (TCD) identifies acute stroke patients with arterial occlusion where treatment may not effectively open the blocked vessel. This study aimed to examine the clinical utility and prognostic value of TCD flow findings in patients enrolled in a multicenter prospective study (CLOTBUST-PRO)., Methods: Patients enrolled with intracranial occlusion on computed tomography angiography (CTA) who underwent urgent TCD evaluation before intravenous thrombolysis was included in this analysis. TCD findings were assessed using the mean flow velocity (MFV) ratio, comparing the reciprocal ratios of the middle cerebral artery (MCA) depths bilaterally (affected MCA-to-contralateral MCA MFV [aMCA/cMCA MFV ratio])., Results: A total of 222 patients with intracranial occlusion on CTA were included in the study (mean age: 64 ± 14 years, 62% men). Eighty-eight patients had M1 MCA occlusions; baseline mean National Institutes of Health Stroke Scale (NIHSS) score was 16, and a 24-hour mean NIHSS score was 10 points. An aMCA/cMCA MFV ratio of <.6 had a sensitivity of 99%, specificity of 16%, positive predictive value (PV) of 60%, and negative PV of 94% for identifying large vessel occlusion (LVO) including M1 MCA, terminal internal carotid artery, or tandem ICA/MCA. Thrombolysis in Brain Ischemia scale, with (grade ≥1) compared to without flow (grade 0), showed a sensitivity of 17.1%, specificity of 86.9%, positive PV of 62%, and negative PV of 46% for identifying LVO., Conclusions: TCD is a valuable modality for evaluating arterial circulation in acute ischemic stroke patients, demonstrating significant potential as a screening tool for intravenous/intra-arterial lysis protocols., (© 2024 The Author(s). Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Aims: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF., Methods and Results: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m 2 , elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials., Conclusions: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Sodium and fluid restriction has traditionally been advocated in patients with heart failure (HF) due to their sodium and water avid state. However, most evidence regarding the altered sodium handling, fluid homeostasis and congestion-related signs and symptoms in patients with HF originates from untreated patient cohorts and physiological investigations. Recent data challenge the beneficial role of dietary sodium and fluid restriction in HF. Consequently, the European Society of Cardiology HF guidelines have gradually downgraded these recommendations over time, now advising for the limitation of salt intake to no more than 5 g/day in patients with HF, while contemplating fluid restriction of 1.5-2 L/day only in selected patients. Therefore, the objective of this clinical consensus statement is to provide advice on fluid and sodium intake in patients with acute and chronic HF, based on contemporary evidence and expert opinion., (© 2024 European Society of Cardiology.)

Background and Purpose: Orolingual angioedema (OA) represents a rare but life-threatening complication among patients with acute ischemic stroke treated with intravenous thrombolysis with alteplase. Novel agents, including icatibant, are recommended in resistant patients with alteplase-induced OA who have failed to respond to first-line therapies including corticosteroids, antihistamines, and/or adrenaline., Methods: We present a patient with alteplase-induced OA who showed substantial clinical improvement following the administration of icatibant., Results: We describe a 71-year-old woman with known arterial hypertension under treatment with angiotensin-converting enzyme inhibitor, who presented with acute ischemic stroke in the territory of the right middle cerebral artery and received intravenous alteplase. During intravenous thrombolysis, the case was complicated with OA without any response to standard anaphylactic treatment including corticosteroids, dimetindene, and adrenaline. Thirty minutes after symptom onset, icatibant, a synthetic selective bradykinin B2-receptor antagonist, was administered subcutaneously. Substantial symptomatic resolution was observed only following the icatibant administration., Conclusions: This case highlights the effectiveness of icatibant in the acute management of alteplase-induced OA. In particular, icatibant administration, following first-line therapies including corticosteroids, antihistamines, and/or adrenaline, may avert tracheostomy and intubation in resistant and refractory cases with OA following intravenous thrombolysis for acute ischemic stroke., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Cardio-oncology is a rapidly growing field of cardiovascular (CV) medicine that has resulted from the continuously increasing clinical demand for specialized CV evaluation, prevention and management of patients suffering or surviving from malignant diseases. Dealing with CV disease in patients with cancer requires special knowledge beyond that included in the general core curriculum for cardiology. Therefore, the European Society of Cardiology (ESC) has developed a special core curriculum for cardio-oncology, a consensus document that defines the level of experience and knowledge required for cardiologists in this particular field. It is structured into 8 chapters, including (i) principles of cancer biology and therapy; (ii) forms and definitions of cancer therapy-related cardiovascular toxicity (CTR-CVT); (iii) risk stratification, prevention and monitoring protocols for CTR-CVT; (iv) diagnosis and management of CV disease in patients with cancer; (v) long-term survivorship programmes and cardio-oncology rehabilitation; (vi) multidisciplinary team management of special populations; (vii) organization of cardio-oncology services; (viii) research in cardio-oncology. The core curriculum aims at promoting standardization and harmonization of training and evaluation in cardio-oncology, while it further provides the ground for an ESC certification programme designed to recognize the competencies of certified specialists., (© 2023 European Society of Cardiology.)

Aims: A high-intensity care (HIC) strategy with rapid guideline-directed medical therapy (GDMT) up-titration and close follow-up visits improved outcomes, compared to usual care (UC), in patients recently hospitalized for acute heart failure (AHF). Hypotension is a major limitation to GDMT implementation. We aimed to assess the impact of baseline systolic blood pressure (SBP) on the effects of HIC versus UC and the role of early SBP changes in STRONG-HF., Methods and Results: A total of 1075 patients hospitalized for AHF with SBP ≥100 mmHg were included in STRONG-HF. For the purpose of this post-hoc analysis, patients were stratified by tertiles of baseline SBP (<118, 118-128, and ≥129 mmHg) and, in the HIC arm, by tertiles of changes in SBP from the values measured before discharge to those measured at 1 week after discharge (≥2 mmHg increase, ≤7 mmHg decrease to <2 mmHg increase, and ≥8 mmHg decrease). The primary endpoint was 180-day heart failure rehospitalization or death. The effect of HIC versus UC on the primary endpoint was independent of baseline SBP evaluated as tertiles (p interaction  = 0.77) or as a continuous variable (p interaction  = 0.91). In the HIC arm, patients with increased, stable and decreased SBP at 1 week reached 83.5%, 76.2% and 75.3% of target doses of GDMT at day 90. The risk of the primary endpoint was not significantly different between patients with different SBP changes at 1 week (adjusted p = 0.46)., Conclusions: In STRONG-HF, the benefits of HIC versus UC were independent of baseline SBP. Rapid GDMT up-titration was performed also in patients with an early SBP drop, resulting in similar 180-day outcome as compared to patients with stable or increased SBP., (© 2024 European Society of Cardiology.)

Aims: The therapeutic mechanism of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on left cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF) is not well-established. This study meta-analysed the impact of SGLT2i on left cardiac structure and function in patients with HFrEF., Methods and Results: Online databases were queried up to April 2023 for trials reporting indicators of left cardiac structure and function in patients with HFrEF treated with SGLT2i. Data from studies were pooled using a random-effects model to derive weighted mean differences (WMDs) and 95% confidence intervals (CIs). Six trials were included (n = 555). Compared with control, SGLT2i significantly improved left ventricular end-diastolic volume (LVEDV; WMD: -17.07 ml [-23.84, -10.31]; p < 0.001), LVEDV index (WMD: -5.62 ml/m 2 [-10.28, -0.97]; p = 0.02), left ventricular end-systolic volume (LVESV; WMD: -15.63 ml [-26.15, -5.12]; p = 0.004), LVESV index (WMD: -6.90 ml/m 2 [-10.68, -3.11]; p = 0.001), left ventricular ejection fraction (WMD: 2.71% [0.70, 4.72]; p = 0.008), and left atrial volume index (WMD: -2.19 ml/m 2 [-4.26, -0.11]; p = 0.04) in patients with HFrEF. SGLT2i use was associated with a non-significant trend towards a reduction in left ventricular mass index (WMD: -6.25 g/m 2 [-12.79, 0.28]; p = 0.06). No significant impact on left ventricular global longitudinal strain was noted (WMD: 0.21% [-0.25, 0.67]; p = 0.38)., Conclusions: Sodium-glucose cotransporter 2 inhibitors improve cardiac structure and function in patients with HFrEF., (© 2024 European Society of Cardiology.)

Aims: There are few prospective reports of 1-year outcomes for women with peripartum cardiomyopathy (PPCM). We report findings from the European Society of Cardiology EURObservational Research Programme PPCM Registry., Methods and Results: The registry enrolled women from 51 countries from 2012 to 2018. Eligibility included: (i) a peripartum state, (ii) signs or symptoms of heart failure, (iii) left ventricular (LV) ejection fraction ≤45%, (iv) exclusion of alternative causes of heart failure. We report mortality, thromboembolism, stroke, rehospitalization, LV recovery and remodelling at 1 year. Differences between regions were compared. One-year mortality data were available in 535 (71%) women and follow-up differed across regions. At 1 year, death from any cause occurred in 8.4% of women, with regional variation (Europe 4.9%, Africa 6.5%, Asia-Pacific 9.2%, Middle East 18.9%; p < 0.001). The frequencies of thromboembolism and stroke were 6.3% and 2.5%, respectively, and were similar across regions. A total of 14.0% of women had at least one rehospitalization and 3.5% had recurrent rehospitalizations (i.e. two or more). Overall, 66.1% of women had recovery of LV function (22% between 6 months and 1 year), with a mean LV ejection fraction increase from baseline of 21.2% (±13.6). Recovery occurred most frequently in Asia-Pacific (77.5%) and least frequently in the Middle East (32.7%). There were significant regional differences in the use of heart failure pharmacotherapies., Conclusions: Approximately 1 in 12 women with PPCM had died by 1 year and thromboembolism and stroke occurred in 6.3% and 2.5%, respectively. Around 1 in 7 women had been rehospitalized and, in 1 in 3, LV recovery had not occurred. PPCM is associated with substantial mortality and morbidity globally., (© 2023 European Society of Cardiology.)

Background and Purpose: Hemorrhagic transformation (HT) has been reported in up to 50% of acute ischemic stroke (AIS) patients with a large vessel occlusion (LVO) treated with endovascular thrombectomy (EVT). HT may be driven by postrecanalization hyperperfusion injury and is independently associated with worse functional outcomes. Strategies to identify patients at risk for HT may assist in developing preventive therapies., Methods: We prospectively included adult AIS patients with an anterior circulation LVO achieving successful recanalization after EVT. Consenting participants received transcranial Doppler ultrasound (TCD) within 18 hours of procedure completion. We compared flow velocities according to the presence of HT on the computed tomography scan performed within the first 24±12 hours from the end of EVT. We also evaluated the association of flow velocities with systemic blood pressure (BP) readings at the time of insonation., Results: A total of 48 patients consented to participate in the study. Six (12%) were excluded due to the absence of temporal windows. HT was detected in 20 participants (48%). Those with HT had higher peak systolic velocities on the middle cerebral arteries compared to those without HT for both the symptomatic (107±42 vs. 82±25 cm/second, p = .024) and asymptomatic (97±21 vs. 81±25 cm/second, p = .040) sides. No correlation of flow velocities on either the symptomatic or asymptomatic side and BP measurements at the time of insonation was detected., Conclusion: TCD can identify patients at risk of HT following successful EVT. TCD could serve as an inexpensive ancillary test to guide participant selection for clinical trials targeting postprocedural reperfusion injury., (© 2023 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Background: Adverse left ventricular (LV) remodelling after myocardial infarction is associated with heart failure. We investigated whether aortic stiffness during acute ST-segment elevation myocardial infarction is associated with LV remodelling at long-term follow-up., Methods: In 109 patients within 48 h of myocardial infarction post-primary percutaneous coronary intervention and after 2 years, we measured: (a) carotid to femoral pulse wave velocity (PWV), (b) LV global longitudinal strain (GLS) and left atrial strain using speckle-tracking echocardiography, (c) PWV/GLS ratio as a surrogate marker of ventricular-arterial interaction, and (d) LV end-diastolic and end-systolic volumes. A > 15% decrease from the baseline in LV end-systolic volume at 2-year follow-up was considered as a criterion of reverse LV remodelling., Results: Compared with baseline, all patients had reduced PWV, LV end-diastolic and end-systolic volumes while PWV/GLS, GLS and reservoir left atrial strain were improved (p < .05) after 2 years. Baseline values of PWV, GLS, PWV/GLS ratio and reservoir left atrial strain were associated with percentage change of LV end-systolic volume at 2 years (p < .05). Multivariable analysis revealed that lower baseline values of PWV and a less impaired GLS and PWV/GLS were independently associated with reverse LV remodelling at 2 years with a C-statistic of .748, .711 and .787, respectively., Conclusion: Aortic stiffness early post-infarction determines LV remodelling after 2 years of the ischemic event despite post successful revascularization., Clinical Trial Registration-Url: http://www., Clinicaltrials: gov. Unique identifier: NCT03984123, 30/04/2020., (© 2023 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Aim: It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high-risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion., Methods and Results: Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR] MRA 0.96, 95% confidence interval [CI] 0.77-1.19 and HR MRA- 0.87, 95% CI 0.71-1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator-reported endpoints were evaluated (p = 0.61 for interaction)., Conclusions: Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post-MI setting in patients with LVSD and/or congestion., (© 2023 European Society of Cardiology.)

Background and Purpose: Transorbital sonography (TOS) provides a noninvasive tool to detect intracranial pressure by assessing optic nerve sheath diameter (ONSD) and optic disc elevation (ODE). The utility of TOS in the diagnosis of idiopathic intracranial hypertension (IIH) has been increasingly recognized., Methods: A single-center case-control study sought to compare TOS-acquired ONSD and ODE among IIH-cases versus patients with other neurological diseases (controls). Furthermore, a systematic review and meta-analysis was conducted to present pooled mean differences and diagnostic measures of ONSD and ODE between IIH-cases and controls., Results: In the single-center study, consisting of 31 IIH-cases and 34 sex- and age-matched controls, ONSD values were higher among IIH-cases than controls (p<.001), while ODE was more prevalent in cases (65% vs. 15%; p<.001). The receiver-operating characteristic (ROC)-curve analysis revealed that the optimal cutoff value of ONSD for predicting IIH was 5.15 mm, with an area under the curve (AUC) of 0.914 (95% confidence interval [CI]: 0.861-0.967) and sensitivity and specificity values of 85% and 90%, respectively. In a meta-analysis of 14 included studies with 415 IIH-cases, ONSD and ODE values were higher in IIH-cases than controls (mean difference in ONSD 1.20 mm; 95% CI: 0.96-1.44 mm and in ODE 0.3 mm; 95% CI: 0.33-0.67 mm). With regard to ONSD, pooled sensitivity, specificity, and diagnostic odds ratio were calculated at 85.5% (95% CI: 77.9-90.8%), 90.7% (95% CI: 84.6-94.5%), and 57.394 (95% CI: 24.597-133.924), respectively. The AUC in summary ROC-curve analysis was 0.878 (95% CI: 0.858-0.899) with an optimal cutoff point of 5.0 mm., Conclusions: TOS has a high diagnostic utility for the noninvasive diagnosis of IIH and may deserve wider implementation in everyday clinical practice., (© 2023 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Cardiomyopathies are a significant contributor to cardiovascular morbidity and mortality, mainly due to the development of heart failure and increased risk of sudden cardiac death (SCD). Despite improvement in survival with contemporary treatment, SCD remains an important cause of mortality in cardiomyopathies. It occurs at a rate ranging between 0.15% and 0.7% per year (depending on the cardiomyopathy), which significantly surpasses SCD incidence in the age- and sex-matched general population. The risk of SCD is affected by multiple factors including the aetiology, genetic basis, age, sex, physical exertion, the extent of myocardial disease severity, conduction system abnormalities, and electrical instability, as measured by various metrics. Over the past decades, the knowledge on the mechanisms and risk factors for SCD has substantially improved, allowing for a better-informed risk stratification. However, unresolved issues still challenge the guidance of SCD prevention in patients with cardiomyopathies. In this review, we aim to provide an in-depth discussion of the contemporary concepts pertinent to understanding the burden, risk assessment and prevention of SCD in cardiomyopathies (dilated, non-dilated left ventricular, hypertrophic, arrhythmogenic right ventricular, and restrictive). The review first focuses on SCD incidence in cardiomyopathies and then summarizes established and emerging risk factors for life-threatening arrhythmias/SCD. Finally, it discusses validated approaches to the risk assessment and evidence-based measures for SCD prevention in cardiomyopathies, pointing to the gaps in evidence and areas of uncertainties that merit future clarification., (© 2023 European Society of Cardiology.)

Aim: In this subgroup analysis of STRONG-HF, we explored the association between changes in renal function and efficacy of rapid up-titration of guideline-directed medical therapy (GDMT) according to a high-intensity care (HIC) strategy., Methods and Results: In patients randomized to the HIC arm (n = 542), renal function was assessed at baseline and during follow-up visits. We studied the association with clinical characteristics and outcomes of a decrease in estimated glomerular filtration rate (eGFR) at week 1, defined as ≥15% decrease from baseline. Patients in the usual care group (n = 536) were seen at day 90. The treatment effect of HIC versus usual care was independent of baseline eGFR (p-interaction = 0.4809). A decrease in eGFR within 1 week occurred in 77 (15.5%) patients and was associated with more rales on examination (p = 0.004), and a higher New York Heart Association class at the corresponding visit. Following the decrease in eGFR at 1 week, lower average optimal doses of GDMT were prescribed during follow-up (p = 0.0210) and smaller reductions in N-terminal pro-B-type natriuretic peptide occurred (geometrical mean 0.81 in no eGFR decrease vs 1.12 in GFR decrease, p = 0.0003). The rate of heart failure (HF) readmission or death at 180 days was 12.3% in no eGFR decrease versus 18.5% in eGFR decrease (p = 0.2274) and HF readmissions were 7.8% versus 16.6% (p = 0.0496)., Conclusions: In the STRONG-HF study, HIC reduced 180-day HF readmission or death regardless of baseline eGFR. An early decrease in eGFR during rapid up-titration of GDMT was associated with more evidence of congestion, yet lower doses of GDMT during follow-up., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: To assess the potential interaction between non-cardiac comorbidities (NCCs) and the efficacy and safety of high-intensity care (HIC) versus usual care (UC) in the STRONG-HF trial, including stable patients with improved but still elevated natriuretic peptides., Methods and Results: In the trial, eight NCCs were reported: anaemia, diabetes, renal dysfunction, severe liver disease, chronic obstructive pulmonary disease/asthma, stroke/transient ischaemic attack, psychiatric/neurological disorders, and malignancies. Patients were classified by NCC number (0, 1, 2 and ≥3). The treatment effect of HIC versus UC on the primary endpoint, 180-day death or heart failure (HF) rehospitalization, was compared by NCC number and by each individual comorbidity. Among the 1078 patients, the prevalence of 0, 1, 2 and ≥3 NCCs was 24.3%, 39.8%, 24.5% and 11.4%, respectively. Achievement of full doses of HF therapies at 90 and 180 days in the HIC was similar irrespective of NCC number. In HIC, the primary endpoint occurred in 10.0%, 16.6%, 13.6% and 26.2%, in those with 0, 1, 2 and ≥3 NCCs, respectively, as compared to 19.1%, 25.4%, 23.3% and 26.2% in UC (interaction-p = 0.80). The treatment benefit of HIC versus UC on the primary endpoint did not differ significantly by each individual comorbidity. There was no significant treatment interaction by NCC number in quality-of-life improvement (p = 0.98) or the incidence of serious adverse events (p = 0.11)., Conclusions: In the STRONG-HF trial, NCCs neither limited the rapid up-titration of HF therapies, nor attenuated the benefit of HIC on the primary endpoint. In the context of a clinical trial, the benefit-risk ratio favours the rapid up-titration of HF therapies even in patients with multiple NCCs., (© 2023 European Society of Cardiology.)

Objective: To characterize its dose-response relationship, BI 655064 (an anti-CD40 monoclonal antibody) was tested as an add-on to mycophenolate and glucocorticoids in patients with active lupus nephritis (LN)., Methods: A total of 121 patients were randomized (2:1:1:2) to receive placebo or BI 655064 120, 180, or 240 mg and received a weekly loading dose for 3 weeks followed by dosing every 2 weeks for the 120 and 180 mg groups, and 120 mg weekly for the 240 mg group. The primary endpoint was complete renal response (CRR) at week 52. Secondary endpoints included CRR at week 26., Results: A dose-response relationship with CRR at week 52 was not shown (BI 655064 120 mg, 38.3%; 180 mg, 45.0%; 240 mg, 44.6%; placebo, 48.3%). At week 26, 28.6% (120 mg), 50.0% (180 mg), 35.0% (240 mg), and 37.5% (placebo) achieved CRR. The unexpected high placebo response prompted a post hoc analysis evaluating confirmed CRR (cCRR, at weeks 46 and 52). cCRR was achieved in 22.5% (120 mg), 44.3% (180 mg), 38.2% (240 mg), and 29.1% (placebo) of patients. Most patients reported ≥1 adverse event (BI 655064, 85.7-95.0%; placebo, 97.5%), most frequently infections and infestations (BI 655064 61.9-75.0%; placebo 60%). Compared with other groups, higher rates of serious (20% vs. 7.5-10%) and severe infections (10% vs. 4.8-5.0%) were reported with 240 mg BI 655064., Conclusion: The trial failed to demonstrate a dose-response relationship for the primary CRR endpoint. Post hoc analyses suggest a potential benefit of BI 655064 180 mg in patients with active LN., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Cardiomyopathies represent significant contributors to cardiovascular morbidity and mortality. Over the past decades, a progress has occurred in characterization of the genetic background and major pathophysiological mechanisms, which has been incorporated into a more nuanced diagnostic approach and risk stratification. Furthermore, medications targeting core disease processes and/or their downstream adverse effects have been introduced for several cardiomyopathies. Combined with standard care and prevention of sudden cardiac death, these novel and emerging targeted therapies offer a possibility of improving the outcomes in several cardiomyopathies. Therefore, the aim of this document is to summarize practical approaches to the treatment of cardiomyopathies, which includes the evidence-based novel therapeutic concepts and established principles of care, tailored to the individual patient aetiology and clinical presentation of the cardiomyopathy. The scope of the document encompasses contemporary treatment of dilated, hypertrophic, restrictive and arrhythmogenic cardiomyopathy. It was based on an expert consensus reached at the Heart Failure Association online Workshop, held on 18 March 2021., (© 2023 European Society of Cardiology.)

Background and Purpose: Several risk factors of symptomatic intracerebral hemorrhage (SICH) following intravenous thrombolysis for acute ischaemic stroke have been established. However, potential predictors of good functional outcome post-SICH have been less studied., Methods: Patient data registered in the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) from 2005 to 2021 were used. Acute ischaemic stroke patients who developed post intravenous thrombolysis SICH according to the SITS Monitoring Study definition were analyzed to identify predictors of functional outcomes., Results: A total of 1679 patients with reported SICH were included, out of which only 2.8% achieved good functional outcome (modified Rankin Scale scores of 0-2), whilst 80.9% died at 3 months. Higher baseline National Institutes of Health Stroke Scale (NIHSS) score and 24-h ΔNIHSS score were independently associated with a lower likelihood of achieving both good and excellent functional outcomes at 3 months. Baseline NIHSS and hematoma location (presence of both SICHs, defined as remote and local SICH concurrently; n = 478) were predictors of early mortality within 24 h. Independent predictors of 3-month mortality were age, baseline NIHSS, 24-h ΔNIHSS, admission serum glucose values and hematoma location (both SICHs). Age, baseline NIHSS score, 24-h ΔNIHSS, hyperlipidemia, prior stroke/transient ischaemic attack, antiplatelet treatment, diastolic blood pressure at admission, glucose values on admission and SICH location (both SICHs) were associated with reduced disability at 3 months (≥1-point reduction across all modified Rankin Scale scores). Patients with remote SICH (n = 219) and local SICH (n = 964) had comparable clinical outcomes, both before and after propensity score matching., Conclusions: Symptomatic intracerebral hemorrhage presents an alarmingly high prevalence of adverse clinical outcomes, with no difference in clinical outcomes between remote and local SICH., (© 2023 European Academy of Neurology.)

Aims: Decongestion strategies for acute decompensated heart failure (ADHF) characterized by volume overload differ widely. The aim of this independent international academic web-based survey was to capture the therapeutic strategies that physicians use to treat ADHF and to assess differences in therapeutic approaches between cardiologists versus non-cardiologists., Methods and Results: Physicians were invited to complete a web-based questionnaire, capturing anonymized data on physicians' characteristics and treatment preferences based on a hypothetical clinical scenario of a patient hospitalized with ADHF. A total of 641 physicians from 60 countries participated. A wide variation in the management of the patient was observed. There was conservative use of diuretics, i.e. only 7% started intravenous furosemide at a dose ≥2 times the baseline oral dose, and infrequent use of ultrasound in assessing congestion (20.4%). Spot urinary sodium was infrequently or never measured by ≥85% of physicians. A third considered a patient with ongoing oedema as being stabilized. There were significant differences between cardiologists and non-cardiologists in the management of ADHF, the targets for daily body weight loss and urine output, diuretic escalation strategies (66.3% vs. 40.7% would escalate diuresis by adding a thiazide) and assessment of response to treatment (27.0% vs. 52.9% considered patients with minimal congestion as stabilized)., Conclusions: There is substantial variability amongst physicians and between cardiologists and non-cardiologists in the management of patients with ADHF, with regard to clinical parameters used to tailor treatment, treatment goals, diuretic dosing and escalation strategies., (© 2023 European Society of Cardiology.)

The delivery of effective healthcare entails the configuration and resourcing of health economies to address the burden of disease, including acute and chronic heart failure, that affects local populations. Increasing migration is leading to more multicultural and ethnically diverse societies worldwide, with migration research suggesting that minority populations are often subject to discrimination, socio-economic disadvantage, and inequity of access to optimal clinical support. Within these contexts, the provision of person-centred care requires medical and nursing staff to be aware of and become adept in navigating the nuances of cultural diversity, and how that can impact some individuals and families entrusted to their care. This paper will examine current evidence, provide practical guidance, and signpost professionals on developing cultural competence within the setting of patients with advanced heart failure who may benefit from palliative care., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Acetazolamide, an inhibitor of proximal tubular sodium reabsorption, leads to more effective decongestion in acute heart failure (AHF). It is unknown whether acetazolamide alters serum sodium and potassium levels on top of loop diuretics and if baseline values modify the treatment effect of acetazolamide., Methods and Results: This is a pre-specified sub-analysis of the ADVOR trial that randomized 519 patients with AHF and volume overload in a 1:1 ratio to intravenous acetazolamide or matching placebo on top of standardized intravenous loop diuretics. Mean potassium and sodium levels at randomization were 4.2 ± 0.6 and 139 ± 4 mmol/L in the acetazolamide arm versus 4.2 ± 0.6 and 140 ± 4 mmol/L in the placebo arm. Hypokalaemia (<3.5 mmol/L) on admission was present in 44 (9%) patients and hyponatraemia (≤135 mmol/L) in 82 (16%) patients. After 3 days of treatment, 44 (17%) patients in the acetazolamide arm and 35 (14%) patients in the placebo arm developed hyponatraemia (p = 0.255). Patients randomized to acetazolamide demonstrated a slight decrease in mean potassium levels during decongestion, which was non-significant over time (p = 0.053) and had no significant impact on hypokalaemia incidence (p = 0.061). Severe hypokalaemia (<3.0 mmol/L) occurred in only 7 (1%) patients, similarly distributed between the two treatment arms (p = 0.676). Randomization towards acetazolamide improved decongestive response irrespective of baseline serum sodium and potassium levels., Conclusions: Acetazolamide on top of standardized loop diuretic therapy does not lead to clinically important hypokalaemia or hyponatraemia and improves decongestion over the entire range of baseline serum potassium and sodium levels., (© 2023 European Society of Cardiology.)

Acute heart failure is a major cause of urgent hospitalizations. These are followed by marked increases in death and rehospitalization rates, which then decline exponentially though they remain higher than in patients without a recent hospitalization. Therefore, optimal management of patients with acute heart failure before discharge and in the early post-discharge phase is critical. First, it may prevent rehospitalizations through the early detection and effective treatment of residual or recurrent congestion, the main manifestation of decompensation. Second, initiation at pre-discharge and titration to target doses in the early post-discharge period, of guideline-directed medical therapy may improve both short- and long-term outcomes. Third, in chronic heart failure, medical treatment is often left unchanged, so the acute heart failure hospitalization presents an opportunity for implementation of therapy. The aim of this scientific statement by the Heart Failure Association of the European Society of Cardiology is to summarize recent findings that have implications for clinical management both in the pre-discharge and the early post-discharge phase after a hospitalization for acute heart failure., (© 2023 European Society of Cardiology.)

Background and Purpose: Cerebral small vessel disease is a common manifestation among patients with Fabry disease (FD). As a biomarker of cerebral small vessel disease, the prevalence of impaired cerebral autoregulation as assessed by transcranial Doppler (TCD) ultrasonography was evaluated in FD patients and healthy controls., Methods: TCD was performed to assess pulsatility index (PI) and vasomotor reactivity expressed by breath-holding index (BHI) for the middle cerebral arteries of included FD patients and healthy controls. Prevalence of increased PI (>1.2) and decreased BHI (<0.69) and ultrasound indices of cerebral autoregulation were compared in FD patients and controls. The potential association of ultrasound indices of impaired cerebral autoregulation with white matter lesions and leukoencephalopathy on brain MRI in FD patients was also evaluated., Results: Demographics and vascular risk factors were similar in 23 FD patients (43% women, mean age: 51 ± 13 years) and 46 healthy controls (43% women, mean age: 51 ± 13 years). The prevalence of increased PI (39%; 95% confidence interval [CI]: 20%-61%), decreased BHI (39%; 95% CI: 20%-61%), and the combination of increased PI and/or decreased BHI (61%; 95% CI: 39%-80%) was significantly (p < .001) higher in FD patients compared to healthy controls (2% [95% CI: 0.1%-12%], 2% [95% CI: 0.1%-12%], and 4% [95% CI: 0.1%-15%], respectively). However, indices of abnormal cerebral autoregulation were not associated independently with white matter hyperintensities and presented a low-to-moderate predictive ability for the discrimination of FD patients with and without white matter hyperintensities., Conclusions: Impaired cerebral autoregulation as assessed by TCD appears to be highly more prevalent among FD patients compared to healthy controls., (© 2023 American Society of Neuroimaging.)

Acute heart failure (AHF) represents a broad spectrum of disease states, resulting from the interaction between an acute precipitant and a patient's underlying cardiac substrate and comorbidities. Valvular heart disease (VHD) is frequently associated with AHF. AHF may result from several precipitants that add an acute haemodynamic stress superimposed on a chronic valvular lesion or may occur as a consequence of a new significant valvular lesion. Regardless of the mechanism, clinical presentation may vary from acute decompensated heart failure to cardiogenic shock. Assessing the severity of VHD as well as the correlation between VHD severity and symptoms may be difficult in patients with AHF because of the rapid variation in loading conditions, concomitant destabilization of the associated comorbidities and the presence of combined valvular lesions. Evidence-based interventions targeting VHD in settings of AHF have yet to be identified, as patients with severe VHD are often excluded from randomized trials in AHF, so results from these trials do not generalize to those with VHD. Furthermore, there are not rigorously conducted randomized controlled trials in the setting of VHD and AHF, most of the data coming from observational studies. Thus, distinct to chronic settings, current guidelines are very elusive when patients with severe VHD present with AHF, and a clear-cut strategy could not be yet defined. Given the paucity of evidence in this subset of AHF patients, the aim of this scientific statement is to describe the epidemiology, pathophysiology, and overall treatment approach for patients with VHD who present with AHF., (© 2023 European Society of Cardiology.)

Background: Hydroxytyrosol reduces low-density lipoprotein oxidation, contributing to prevention of atherosclerosis progression., Methods: In a prospective, crossover, double-blind, placebo-controlled trial, 30 chronic coronary artery syndrome (CCAS) patients were randomized to 4 capsules/day, containing 412.5 mg olive oil with 2.5 mg hydroxytyrosol (OOHT) each one or placebo for 1 month and then were crossed over to the alternate treatment (placebo or OOHT). We measured (a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), (b) flow-mediated dilation (FMD), (c) Coronary Flow Reserve (CFR) and markers of LV diastolic function by Doppler echocardiography, (d) pulse wave velocity (PWV), and (e) oxidative stress, inflammatory biomarkers and blood lipids at baseline and after treatment., Results: Treatment with OOHT improved PBR, FMD, CFR and PWV compared to baseline (1.8 ± .3 vs. 1.7 ± .4 μm, p = .040, 3.7 ± 2.1 vs. 6.5% ± 2.3%, p < .001, 2.3 ± .4 vs. 2.5 ± .4, p = .030 and 11.1 ± 1.8 vs. 11.8 ± 2.3 m/s, p = .002) while there was no effect after placebo (p = NS). No effect of OOHT treatment was observed on blood pressure. There was a parallel improvement of E' of the mitral annulus and deceleration time of the E wave of mitral inflow after OOHT (p < .05) but not after placebo. Compared to baseline, treatment with OOHT reduced malondialdehyde, a marker of lipid peroxidation, oxidized LDL, triglycerides, PCSK9 and CRP blood levels (p < .05) in contrast to placebo., Conclusions: Hydroxytyrosol-enriched olive oil may have beneficial effects on endothelial, arterial and LV diastolic function likely by reducing oxidative and inflammatory burden in CCAS, though further studies are needed to confirm this mechanism., (© 2023 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Aims: STRONG-HF examined a high-intensity care (HIC) strategy of rapid up-titration of guideline-directed medical therapy (GDMT) and close follow-up after acute heart failure (AHF) admission. We assess the role of age on efficacy and safety of HIC., Methods and Results: Hospitalized AHF patients, not treated with optimal GDMT were randomized to HIC or usual care. The primary endpoint of 180-day death or HF readmission occurred equally in older (>65 years, n = 493, 74 ± 5 years) and younger patients (53 ± 11 years, adjusted hazard ratio [aHR] 1.02, 95% confidence interval [CI] 0.73-1.43, p = 0.89). Older patients received slightly lower GDMT to day 21, but same doses at day 90 and 180. The effect of HIC on the primary endpoint was numerically higher in younger (aHR 0.51, 95% CI 0.32-0.82) than older patients (aHR 0.73, 95% CI 0.46-1.15, adjusted interaction p = 0.30), partially related to COVID-19 deaths. After exclusion of COVID-19 deaths, the effect of HIC was similar in younger (aHR 0.51, 95% CI 0.32-0.82) and older patients (aHR 0.63, 95% CI 0.32-1.02, adjusted interaction p = 0.56), with no treatment-by-age interaction (interaction p = 0.57). HIC induced larger improvements in quality of life to day 90 in younger (EQ-VAS adjusted-mean difference 5.51, 95% CI 3.20-7.82) than in older patients (1.77, 95% CI -0.75 to 4.29, interaction p = 0.032). HIC was associated with similar rates of adverse events in older and younger patients., Conclusion: High-intensity care after AHF was safe and resulted in a significant reduction of all-cause death or HF readmission at 180 days across the study age spectrum. Older patients have smaller benefits in terms of quality of life., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The aim of this study was to evaluate efficacy and safety of rapid up-titration of guideline-directed medical therapies (GDMT) in men and women hospitalized for acute heart failure (AHF)., Methods and Results: In STRONG-HF, AHF patients were randomized just prior to discharge to either usual care (UC) or a high-intensity care (HIC) strategy of GDMT up-titration. In these analyses, we compared the implementation, efficacy, and safety of the HIC strategy between men and women. In the randomized AHF population, 416/1078 (39%) were women. By day 90, a higher proportion of both sexes in the HIC group had been up-titrated to full doses of GDMT compared to UC. Overall, there were no differences in the primary endpoint between the sexes. The primary endpoint, 180-day heart failure readmission or death, occurred in 15.8% HIC women versus 23.5% women in the UC group (adjusted hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.40-1.13) and in 14.9% HIC men versus 23.5% UC men (adjusted HR 0.57, 95% CI 0.38-0.88) (adjusted interaction p = 0.65). There was no significant treatment-by-sex interaction in quality-of-life improvement or in adverse events, including serious or fatal adverse events., Conclusion: The results of the current analyses suggest that a rapid up-titration of GDMT immediately after an AHF hospitalization can and should be implemented similarly in men and women, as it results in reduction of 180-day all-cause death or heart failure readmission, quality-of-life improvement in both men and women with a similar safety profile., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Episodes of worsening symptoms and signs characterize the clinical course of patients with chronic heart failure (HF). These events are associated with poorer quality of life, increased risks of hospitalization and death and are a major burden on healthcare resources. They usually require diuretic therapy, either administered intravenously or by escalation of oral doses or with combinations of different diuretic classes. Additional treatments may also have a major role, including initiation of guideline-recommended medical therapy (GRMT). Hospital admission is often necessary but treatment in the emergency service or in outpatient clinics or by primary care physicians has become increasingly used. Prevention of first and recurring episodes of worsening HF is an essential component of HF treatment and this may be achieved through early and rapid administration of GRMT. The aim of the present clinical consensus statement by the Heart Failure Association of the European Society of Cardiology is to provide an update on the definition, clinical characteristics, management and prevention of worsening HF in clinical practice., (© 2023 European Society of Cardiology.)

Aim: Evidence on healthcare resource utilization (HCRU) for hospitalized patients with heart failure (HF) and reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction is limited., Methods and Results: We analysed HCRU in relation to left ventricular ejection fraction (LVEF) phenotypes, clinical features and in-hospital and 12-month outcomes in 16 943 patients hospitalized for HF in a worldwide registry. HFrEF was more prevalent (53%) than HFmrEF (17%) or HFpEF (30%). Patients with HFmrEF and HFpEF were older, more often women, with milder symptoms and more comorbidities, but differences were not pronounced. HCRU was high in all three groups; two or more in- and out-of-hospital services were required by 51%, 49% and 52% of patients with HFrEF, HFmrEF and HFpEF, respectively, and intensive care unit by 41%, 41% and 37%, respectively. Hospitalization length was similar (median, 8 days). Discharge prescription of neurohormonal inhibitors was <80% for each agent in HFrEF and only slightly lower in HFmrEF and HFpEF (74% and 67%, respectively, for beta-blockers). Compared to HFrEF, 12-month all-cause and cardiovascular mortality were lower for HFmrEF (adjusted hazard ratios 0.78 [95% confidence interval 0.59-0.71] and 0.80 [0.70-0.92]) and HFpEF (0.64 [0.59-0.87] and 0.63 [0.56-0.71]); 12-month HF hospitalization was also lower for HFpEF and HFmrEF (21% and 20% vs. 25% for HFrEF). In-hospital mortality, 12-month non-cardiovascular mortality and 12-month all-cause hospitalization were similar among groups., Conclusions: In patients hospitalized for HF, overall HCRU was similarly high across LVEF spectrum, reflecting the subtle clinical differences among LVEF phenotypes during hospitalization. Discharge prescription of neurohormonal inhibitors was suboptimal in HFrEF and lower but significant in patients with HFpEF and HFmrEF, who had better long-term cardiovascular outcomes than HFrEF, but similar risk for non-cardiovascular events., (© 2023 European Society of Cardiology.)

Background and Purpose: Two early basilar artery occlusion (BAO) randomized controlled trials did not establish the superiority of endovascular thrombectomy (EVT) over medical management. While many providers continue to recommend EVT for acute BAO, perceptions of equipoise in randomizing patients with BAO to EVT versus medical management may differ between clinician specialties., Methods: We conducted an international survey (January 18, 2022 to March 31, 2022) regarding management strategies in acute BAO prior to the announcement of two trials indicating the superiority of EVT, and compared responses between interventionalists (INTs) and non-interventionalists (nINTs). Selection practices for routine EVT and perceptions of equipoise regarding randomizing to medical management based on neuroimaging and clinical features were compared between the two groups using descriptive statistics., Results: Among the 1245 respondents (nINTs = 702), INTs more commonly believed that EVT was superior to medical management in acute BAO (98.5% vs. 95.1%, p < .01). A similar proportion of INTs and nINTs responded that they would not randomize a patient with BAO to EVT (29.4% vs. 26.7%), or that they would only under specific clinical circumstances (p = .45). Among respondents who would recommend EVT for BAO, there was no difference in the maximum prestroke disability, minimum stroke severity, or infarct burden on computed tomography between the two groups (p > .05), although nINTs more commonly preferred perfusion imaging (24.2% vs. 19.7%, p = .04). Among respondents who indicated they would randomize to medical management, INTs were more likely to randomize when the National Institutes of Health Stroke Scale was ≥10 (15.9% vs. 6.9%, p < .01)., Conclusions: Following the publication of two neutral clinical trials in BAO EVT, most stroke providers believed EVT to be superior to medical management in carefully selected patients, with most indicating they would not randomize a BAO patient to medical treatment. There were small differences in preference for advanced neuroimaging for patient selection, although these preferences were unsupported by clinical trial data at the time of the survey., (© 2023 American Society of Neuroimaging.)

Background and Purpose: The best reperfusion treatment for patients with mild acute ischaemic stroke harbouring proximal anterior circulation large vessel occlusion (LVO) is unknown. The aim was to compare the safety and efficacy of intravenous thrombolysis (IVT) plus endovascular thrombectomy (EVT) versus IVT alone in LVO patients with mild symptoms., Methods: From the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis and Thrombectomy Register (SITS-ISTR), were included: (i) consecutive acute ischaemic stroke patients, (ii) treated within 4.5 h from symptoms onset, (iii) baseline National Institutes of Health Stroke Scale (NIHSS) score ≤5 and (iv) intracranial internal carotid artery [ICA], M1 or T occlusion [defined as occlusion of ICA terminal bifurcation]. After propensity score matching, 3-month functional outcomes (modified Rankin Scale [mRS] 0-1 and 0-2) and safety outcomes (symptomatic intracerebral haemorrhage and death) were compared (via univariable and multivariable logistic [and ordinal] regression analyses) in patients treated with IVT + EVT versus IVT alone., Results: In all, 1037 patients were included. After propensity score matching (n = 312 per group), IVT + EVT was independently associated with poor functional outcomes (adjusted odds ratio [aOR] 0.46 for mRS 0-1, 95% confidence interval [CI] 0.30-0.72, p = 0.001; aOR 0.52 for mRS 0-2, 95% CI 0.32-0.84, p = 0.007; aOR 1.61 for 1-point shift in mRS score, 95% CI 1.12-2.32, p = 0.011), with no significant differences in safety outcomes compared to IVT alone, despite numerically higher rates of symptomatic intracerebral haemorrhage (3.3% vs. 1.1%; p = 0.082), a higher rate of any haemorrhagic transformation (17.6% vs. 7.3%; p < 0.001) and subarachnoid haemorrhage (7.9% vs. 1.5%; p = 0.002) in the IVT + EVT group., Discussion: In anterior circulation LVO patients presenting with NIHSS score ≤5, IVT + EVT (vs. IVT alone) was associated with poorer 3-month functional outcome. Randomized controlled trials are needed to elucidate the best treatments in mild LVO patients., (© 2023 European Academy of Neurology.)

Objective: Contrary to patients, the psychological impact of functional seizures to caregivers has not been adequately investigated. This study aimed to evaluate the rates and determinants of depression and anxiety in caregivers of patients with functional seizures., Methods: Patients with functional seizures and their caregivers completed surveys about demographic, disease-related, and psychosocial characteristics. Rates and determinants of depression and anxiety were evaluated using the Beck Depression and Anxiety Inventory scores as dependent variables and patient and caregiver characteristics as independent variables., Results: Twenty-nine patients (76% female, mean age of 37 years) and their caregivers (59% female, mean age of 43 years) were recruited. Symptoms of anxiety and/or depression were present in 96% of patients (96% depression, 92% anxiety) and 59% of caregivers (52% depression, 50% anxiety). Specifically, 31% of caregivers manifested mild depression, 14% moderate depression, and 7% severe depression, whereas 48% were not depressed. Similarly, 14% of caregivers manifested mild anxiety, 29% moderate anxiety, and 7% severe anxiety, whereas 50% were not anxious. Patient and caregiver depression levels strongly correlated (r = .73, p < .0001). The presence of anxiety and depression in the caregiver was associated with male patient gender (p = .02), patient depression level (p = .002), the caregiver being a parent or sibling (p = .02), and caregiver burden (p = .0009)., Significance: Caregivers of patients with functional seizures experience high rates of anxiety and depression, explained by specific demographic and psychosocial factors that could act as intervention targets., (© 2023 International League Against Epilepsy.)

This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline-directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end-of-life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support)., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The impact of mitral regurgitation (MR) in patients hospitalized for acute heart failure (AHF) is not well established. We assessed the role of MR in patients enrolled in the Relaxin in Acute Heart Failure 2 (RELAX-AHF-2) trial., Methods and Results: Patients enrolled in RELAX-AHF-2 with available data regarding MR status were included in this analysis. Baseline characteristics, in-hospital data, and clinical outcomes through 180-day follow-up were evaluated. The impact of moderate/severe MR was assessed. Among 6420 AHF patients with known MR status, 1810 patients (28.2%) had moderate/severe MR. Compared to patients with no/mild MR, those with moderate/severe MR were more likely to have history of heart failure (HF), prior HF hospitalization, more comorbidities, symptoms/signs of HF, lower left ventricular ejection fraction and higher N-terminal pro-B-type natriuretic peptide levels. Moderate/severe MR was associated with longer length of hospital stay, higher rates of residual dyspnoea, increased jugular venous pressure through the index hospitalization and a higher unadjusted risk of the composite of cardiovascular (CV) death or rehospitalization for HF/renal failure (RF) through 180 days (crude hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.03-1.27, p = 0.01). The association between moderate/severe MR and poorer outcomes was not maintained in a multivariable model including several covariates of interest (adjusted HR 1.03, 95% CI 0.91-1.17, p = 0.65). Similar findings were observed for HF/RF rehospitalization alone., Conclusions: In patients with AHF, moderate/severe MR was associated with a worse clinical profile but did not have an independent prognostic impact on clinical outcomes., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

MASK-air ® , a validated mHealth app (Medical Device regulation Class IIa) has enabled large observational implementation studies in over 58,000 people with allergic rhinitis and/or asthma. It can help to address unmet patient needs in rhinitis and asthma care. MASK-air ® is a Good Practice of DG Santé on digitally-enabled, patient-centred care. It is also a candidate Good Practice of OECD (Organisation for Economic Co-operation and Development). MASK-air ® data has enabled novel phenotype discovery and characterisation, as well as novel insights into the management of allergic rhinitis. MASK-air ® data show that most rhinitis patients (i) are not adherent and do not follow guidelines, (ii) use as-needed treatment, (iii) do not take medication when they are well, (iv) increase their treatment based on symptoms and (v) do not use the recommended treatment. The data also show that control (symptoms, work productivity, educational performance) is not always improved by medications. A combined symptom-medication score (ARIA-EAACI-CSMS) has been validated for clinical practice and trials. The implications of the novel MASK-air ® results should lead to change management in rhinitis and asthma., (© 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Aim: Acute heart failure can be a life-threatening medical condition. Delaying administration of intravenous furosemide (time-to-diuretics) has been postulated to increase mortality, but prior reports have been inconclusive. We aimed to evaluate the association between time-to-diuretics and mortality in the international REPORT-HF registry., Methods and Results: We assessed the association of time-to-diuretics within the first 24 h with in-hospital and 30-day post-discharge mortality in 15 078 patients from seven world regions in the REPORT-HF registry. We further tested for effect modification by baseline mortality risk (ADHERE risk score), left ventricular ejection fraction (LVEF) and region. The median time-to-diuretics was 67 (25th-75th percentiles 17-190) min. Women, patients with more signs and symptoms of heart failure, and patients from Eastern Europe or Southeast Asia had shorter time-to-diuretics. There was no significant association between time-to-diuretics and in-hospital mortality (p > 0.1). The 30-day mortality risk increased linearly with longer time-to-diuretics (administered between hospital arrival and 8 h post-hospital arrival) (p = 0.016). This increase was more significant in patients with a higher ADHERE risk score (p interaction  = 0.008), and not modified by LVEF or geographic region (p interaction  > 0.1 for both)., Conclusion: In REPORT-HF, longer time-to-diuretics was not associated with higher in-hospital mortality. However, we did found an association with increased 30-day mortality, particularly in high-risk patients, and irrespective of LVEF or geographic region., Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02595814., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The aim of this systematic review and meta-analysis was to critically assess the published literature related to community-acquired viral co-infections and COVID-19 and to evaluate the prevalence, most identified co-pathogens, and relevant risk factors. Furthermore, we aimed to examine the clinical features and outcomes of co-infected compared to mono-infected COVID-19 patients. We systematically searched PubMed, Web of Science, Embase, Scopus, and The Cochrane Library for studies published from 1 November 2019 to 13 August 2021. We included patients of all ages and any COVID-19 severity who were screened for respiratory viral co-infection within 48 h of COVID-19 diagnosis. The main outcome was the proportion of patients with a respiratory viral co-infection. The systematic review was registered to PROSPERO (CRD42021272235). Out of 6053 initially retrieved studies, 59 studies with a total of 16,643 SARS-CoV-2 positive patients were included. The global pooled prevalence was 5.01% (95% CI 3.34%-7.27%; I 2  = 95%) based on a random-effects model, with Influenza Viruses (1.54%) and Enteroviruses (1.32%) being the most prevalent pathogens. Subgroup analyses showed that co-infection was significantly higher in paediatric (9.39%) than adult (3.51%) patients (p-value = 0.02). Furthermore, co-infected patients were more likely to be dyspnoeic and the odds of fatality (OR = 1.66) were increased. Although a relatively low proportion of COVID-19 patients have a respiratory viral co-infection, our findings show that multiplex viral panel testing may be advisable in patients with compatible symptoms. Indeed, respiratory virus co-infections may be associated with adverse clinical outcomes and therefore have therapeutic and prognostic implications., (© 2022 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.)

Aims: Limited data exist regarding the prognostic relevance of changes in left atrial (LA) dimensions in patients with heart failure (HF). We assessed changes in LA dimension and their relation with outcomes after optimization of guideline-directed medical therapy (GDMT) in patients with new-onset or worsening HF., Methods and Results: Left atrial diameter was assessed at baseline and 9 months after GDMT optimization in 632 patients (mean age 65.8 ± 12.1 years, 22.3% female) enrolled in BIOSTAT-CHF. LA adverse remodelling (LAAR) was defined as an increase in LA diameter on transthoracic echocardiography between baseline and 9 months. After the 9-month visit, patients were followed for a median of 13 further months. LAAR was observed in 247 patients (39%). Larger baseline LA diameter (odds ratio [OR] 0.90; 95% confidence interval [CI] 0.87-0.93; p < 0.001) and up-titration to higher doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARBs) (OR 0.56; 95% CI 0.34-0.92; p = 0.022) were independently associated with lower likelihood of LAAR. LAAR was associated with an increased risk of the composite of all-cause mortality or HF hospitalization (log-rank p = 0.007 and adjusted hazard ratio 1.73, 95% CI 1.22-2.45, p = 0.002). The association was more pronounced in patients without a history of atrial fibrillation (p for interaction = 0.009)., Conclusion: Among patients enrolled in BIOSTAT-CHF, LAAR was associated with an unfavourable outcome and was prevented by ACEi/ARB up-titration. Changes in LA dimension may be a useful marker of response to treatment and improve risk stratification in patients with HF., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)