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Cardiac amyloidosis is an infiltrative cardiomyopathy characterized by the extracellular deposition of amyloid fibrils within the myocardium. Beyond heart failure, patients with cardiac amyloidosis commonly present with arrhythmias and conduction system disorders. Atrial fibrillation is observed in up to 80% of patients at the time of diagnosis, with patients typically maintaining normal heart rates due to concurrent atrioventricular nodal disease. The thromboembolic risk is particularly high in patients with cardiac amyloidosis, and left atrial thrombi have been observed even in the absence of atrial fibrillation. Conduction system diseases are also highly prevalent, often necessitating permanent pacemaker implantation. The use of implantable defibrillators in this population remains controversial. This overview of published data and therapeutic strategies related to arrhythmias and conduction system disorders aims to assist readers in decision-making in complex clinical scenarios., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Competing Interests: Funding Support and Author Disclosures Dr Settelmeier has received support from the German Research Foundation (UMEA Junior Clinician Scientist, UMEA Clinician Scientist Academy, FU356/12-2). Dr Varasteh has received support from the German Research Foundation (VA1183/2-1). Dr Rischpler has received a research grant from Pfizer; has received consultancy fees for Adacap and Pfizer; and has received speaker honoraria from Adacap, Alnylam, BTG, Curium, GE Healthcare, Pfizer, and Siemens Healthineers outside of the submitted work. Prof Fendler has received fees from SOFIE Bioscience (research funding), Janssen (consultant and speaker), Calyx (consultant and image review), Bayer (consultant, speaker, and research funding), Novartis (speaker and consultant), Telix (speaker), GE Healthcare (speaker), Eczacıbaşı Monrol (speaker), Abx (speaker), Amgen (speaker), and Urotrials (speaker) outside of the submitted work. Prof Umutlu has served as a speaker/Advisory Board member for Bayer Healthcare and Siemens Healthcare; and has received research grants from Siemens Healthcare outside of the submitted work. Prof Herrmann has received consultant fees from Advanced Accelerator Applications (a Novartis company), Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien München, Janssen, Merck, Molecular Partners, NVision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, Sofie Biosciences, Telix, Theragnostics, and Y-mAbs; has received research grants from Advanced Accelerator Applications (a Novartis company), Boston Scientific, and Janssen; and holds stock or other ownership interests in AdvanCell, Aktis Oncology, Convergent, NVision, Pharma 15, and Sofie Biosciences outside of the submitted work. Prof Rassaf is supported by the German Research Foundation (DFG RA969/12-1), Ministry of Science and Culture REBIRTH I/II (ZN3440), and Stiftung Gerdes outside of the submitted work. Dr Kersting has received support from the German Research Foundation (UMEA Clinician Scientist Academy, FU356/12-2); has received a research grant from Pfizer; has received funding by the German Research Foundation (DFG, KE2933/1-1); and has received speaker honoraria from Pfizer outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Approximately one-third of sudden cardiac deaths in the young (SCDY) occur due to a structural cardiac disease. Forty to fifty percent of SCDY cases remain unexplained after autopsy (including microscopic and forensic-toxicological analyses), suggesting arrhythmia syndromes as a possible cause of death. Due to the possible inheritability of these diseases, blood relatives of the deceased may equally be carriers of the causative genetic variations and therefore may have an increased cardiac risk profile. A better understanding of the forensic, clinical, and genetic data might help identify a subset of the general population that is at increased risk of sudden cardiac death., Study Design: The German registry RESCUED (REgistry for Sudden Cardiac and UnExpected Death) comprises information about SCDY fatalities and clinical and genetic data of both the deceased and their biological relatives. The datasets collected in the RESCUED registry will allow for the identification of leading causes of SCDY in Germany and offer unique possibilities of scientific analyses with the aim of detecting unrecognized trends, risk factors, and clinical warning signs of SCDY. In a pilot phase of 24 months, approximately 180 SCDY cases (< 50 years of age) and 500 family members and clinical patients will be included., Conclusion: RESCUED is the first registry in Germany collecting comprehensive data of SCDY cases and clinical data of the biological relatives reviewed by cardiac experts. RESCUED aims to improve individual risk assessment and public health approaches by directing resources towards early diagnosis and evidence-based, personalized therapy and prevention in affected families. Trial registration number (TRN): DRKS00033543., (© 2024. The Author(s).)

Aims: The optimal strategy to identify transthyretin-type cardiac amyloidosis (ATTR-CA) in patients with aortic stenosis (AS) is still unclear. This study aimed to investigate if targeted screening for ATTR-CA in patients with severe AS and amyloid red flags is associated with higher detection rates., Methods: The study prospectively enrolled patients ≥65 years with severe AS. Patients who fulfilled ≥1 major (carpal tunnel syndrome (CTS), ruptured biceps tendon, spinal stenosis, N-terminal pro B-type natriuretic peptide ≥1000 pg/mL, cardiac troponin >99th percentile) or ≥2 minor criteria (diastolic dysfunction ≥2 grade/lateral e' <10 cm/s, atrial fibrillation, atrioventricular conduction disease/pacemaker) received bone scintigraphy and biochemical analysis for light chain amyloidosis. Hypertensive patients (>140/90 mmHg) and those with interventricular septal thickness (IVSd) ≤13 mm were excluded., Results: Overall, 264 patients were screened, of whom 85 were included in the analysis. Tracer uptake Perugini grade ≥1 was detected in nine patients (11%). An endomyocardial biopsy was additionally performed in four of nine patients, yielding a prevalence of 7% (n = 6). All patients with dual AS-ATTR were male. Syncope was more commonly reported in AS-ATTR patients (50% vs. 6%, p = 0.010), who also tended to have more severe hypertrophy (IVSd of 18 vs. 16 mm, p = 0.075). Pericardial effusion and CTS were more common in patients with dual pathology (67% vs. 8%, p < 0.001, and 83% vs. 24%, p = 0.003, respectively)., Conclusion: Targeted screening for ATTR-CA in patients with AS and amyloid red flags does not yield higher detection rates than those reported previously in all comers with AS.

Treatment of patients with Mayo stage IIIb light chain (AL) amyloidosis is still challenging, and the prognosis remains very poor. Mayo stage IIIb patients were excluded from the pivotal trial leading to the approval of daratumumab in combination with bortezomib-cyclophosphamide-dexamethasone. This retrospective, multicenter study evaluates the addition of daratumumab to first-line therapy in patients with newly diagnosed stage IIIb AL amyloidosis. In total, data from 119 consecutive patients were analyzed, 27 patients received an upfront treatment including daratumumab, 63 a bortezomibbased regimen without daratumumab, eight received therapies other than daratumumab or bortezomib and 21 pretreated patients or deceased prior to treatment were excluded. In the daratumumab group, median overall survival was not reached after a median follow-up time of 14.5 months, while it was significantly worse in the bortezomib- and the otherwise treated group (6.6 and 2.2 months, respectively) (P=0.002). Overall hematologic response rate at 2 and 6 months was better in the daratumumab group compared to the bortezomib group (59% vs. 37%, P=0.12, 67% vs. 41%, P=0.04, respectively). Landmark survival analyses revealed a significantly improved overall survival in patients with partial hematologic response or better, compared to non-responders. Cardiac response at 6 months was 46%, 21%, 0% in the daratumumab-, bortezomib- and otherwise treated groups, respectively (P=0.04). A landmark survival analysis revealed markedly improved overall survival in patients with cardiac very good partial response vs. cardiac non-responders (P=0.002). This study demonstrates for the first time the superiority of an upfront treatment with daratumumab over standard-of-care in stage IIIb AL amyloidosis.

Background: Congenital CMV infection (cCMV) is the most common congenital infection with 10-15% of cases developing symptomatic disease. Early antiviral treatment is of essence when symptomatic disease is suspected. Recently, the use of neonatal imaging has been implicated as a prognostic tool for long term sequalae among asymptomatic newborns at high risk. Even though neonatal MRI is commonly used in neonatal symptomatic cCMV disease, it is less often used in asymptomatic newborns, mainly due to cost, access and difficulty to perform. We have therefore developed an interest in assessing the use of fetal imaging as an alternative. Our primary aim was to compare the fetal and neonatal MRIs in a small cohort 10 asymptomatic neonates with congenital CMV infection., Methods: We performed a single-center retrospective cohort study (case-series) on a convenience sample of children born from January 2014 to March 2021 with confirmed congenital CMV infection who had undergone both fetal and neonatal MRIs. We created a checklist of relevant cerebral abnormalities and asked 4 blinded radiologists to assess the MRIs (2 for each, namely fetal and neonatal) and then compared the findings between the fetal and neonatal imaging as well as the concordance in reporting of abnormalities within each category., Findings: Overall concordance between prenatal and postnatal scans was high (70%). When comparing the two blinded reports for each MRI, we found high levels of concordance: 90% concordance for fetal MRIs and 100% for neonatal MRIs. The most common abnormalities identified in both fetal and neonatal scans were "abnormal white matter hyperintensity" and "subependymal cysts.", Interpretation: Even though this is a small descriptive study, it indicates that fetal MRI could potentially provide us with similar information as neonatal imaging. This study could form the basis for subsequent larger future studies.

CYLD is a tumor suppressor gene coding for a deubiquitinating enzyme that has a critical regulatory function in a variety of signaling pathways and biological processes involved in cancer development and progression, many of which are also key modulators of somatic cell reprogramming. Nevertheless, the potential role of CYLD in this process has not been studied. With the dual aim of investigating the involvement of CYLD in reprogramming and developing a better understanding of the intricate regulatory system governing this process, we reprogrammed control ( CYLD WT/WT ) and CYLD DUB-deficient ( CYLD Δ9/Δ9 ) mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs) through ectopic overexpression of the Yamanaka factors (Oct3/4, Sox2, Klf4, c-myc). CYLD DUB deficiency led to significantly reduced reprogramming efficiency and slower early reprogramming kinetics. The introduction of WT CYLD to CYLD Δ9/Δ9 MEFs rescued the phenotype. Nevertheless, CYLD DUB-deficient cells were capable of establishing induced pluripotent colonies with full spontaneous differentiation potential of the three germ layers. Whole proteome analysis (Data are available via ProteomeXchange with identifier PXD044220) revealed that the mesenchymal-to-epithelial transition (MET) during the early reprogramming stages was disrupted in CYLD Δ9/Δ9 MEFs. Interestingly, differentially enriched pathways revealed that the primary processes affected by CYLD DUB deficiency were associated with the organization of the extracellular matrix and several metabolic pathways. Our findings not only establish for the first time CYLD's significance as a regulatory component of early reprogramming but also highlight its role as an extracellular matrix regulator, which has profound implications in cancer research.

Given the limited real-world data of caplacizumab, our multicenter real-world study was designed to assess the safety and efficacy of caplacizumab in immune thrombotic thrombocytopenic pupura (iTTP), compared to historic controls. We have studied 70 patients: 23 in the caplacizumab and 47 in the historic control group. Plasma exchange was applied in all episodes except for two patients that denied plasma exchange. Rituximab as first-line treatment was more common in the caplacizumab group compared to historic control. Caplacizumab (10 mg daily) was given at a median on day 7 (1-43) from initial diagnosis for 32 (6-47) dosages. In the caplacizumab group, a median of 12 (8-23) patients required plasma exchange sessions versus 14 (6-32) in the control group. Caplacizumab administration did not produce any grade 3 complications or major hemorrhagic events. After a median of 19.0 (2.6-320) months since the iTTP diagnosis, 5 deaths occurred (4 in the control group and 1 in the caplacizumab group, p  = 0.310). Caplacizumab patients achieved early platelet normalization and ADAMTS13 activity normalization at the end of treatment. Relapse was observed only in 2/23 (9%) caplacizumab patients, compared to 29/47 (62%) historic controls ( p  < 0.001). Overall, caplacizumab is safe and effective in treating iTTP, including cases refractory to plasma exchange, re-administration, and cases without previous plasma exchange treatment. No major hemorrhagic events were observed. Cessation of dosing guided by ADAMTS13 has ensured a low relapse rate., Competing Interests: AntS and ArgS have received grants, honoraria or travel support from Abbvie, Amgen, Bei-Gene, BMS, Gilead, Glaxo, Janssen, MSD, Pfizer, Roche, Sanofi, Servier, SOBI, Takeda. ChaK and ChrK have received honoraria from Pfizer, BMS, Bayer, Takeda. EG and CP have received honoraria from Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gavriilaki, Nikolousis, Koravou, Dimou-Besikli, Kartsios, Papakonstantinou, Mpanti, Pontikoglou, Kalpadaki, Bitsani, Tassi, Touloumenidou, Chatziconstantinou, Papathanasiou, Syrigou, Ztriva, Kaiafa, Mandala, Mellios, Karakasis, Kourakli, Symeonidis, Kapsali, Papadaki, Lalayanni and Sakellari.)

Aims: Pulmonary capillary wedge pressure (PAWP) ≥25 mmHg during bicycle ergometry is recommended to uncover occult heart failure with preserved ejection fraction. We hypothesized that PAWP increase would differ in available diastolic stress tests and that the margin of PAWP ≥25 mmHg would only be reliably achieved through ergometry., Methods and Results: We conducted a prospective, single-arm study in patients with an intermediate risk for heart failure with preserved ejection fraction according to the ESC HFA-PEFF score. A total of 19 patients underwent four stress test modalities in randomized order: leg raise, fluid challenge, handgrip, and bicycle ergometry. The primary outcome was the difference (Δ) between resting and exercise PAWP in each modality. Secondary outcomes were differences (Δ) in mean pulmonary artery pressure (mPAP), cardiac output (CO), as well as the ratios between mPAP and PAWP to CO. Compared to resting values, passive leg raise (Δ7.7 ± 8.0 mmHg, p = 0.030), fluid challenge (Δ9.2 ± 6.4 mmHg, p = 0.003), dynamic handgrip (Δ9.6 ± 7.5 mmHg, p = 0.002), and bicycle ergometry (Δ22.3 ± 5.0 mmHg, p < 0.001) uncovered increased PAWP during exercise. Amongst these, bicycle ergometry also demonstrated the highest ΔmPAP (27.2 ± 7.1 mmHg, p < 0.001), ΔCO (3.3 ± 2.6 L/min, p < 0.001), ΔmPAP/CO ratio (2.3 ± 2.0 mmHg/L/min, p < 0.001), and ΔPAWP/CO ratio (2.2 ± 1.4 mmHg/L/min, p < 0.001) compared to other modalities. PAWP ≥25 mmHg was only reliably achieved in bicycle ergometry (31.1 ± 3.9 mmHg). In all other modalities only 10.5% of patients achieved PAWP ≥25 mmHg (handgrip 18.4 ± 6.6 mmHg, fluid 18.1 ± 5.6 mmHg, leg raise 16.5 ± 7.0 mmHg)., Conclusions: We demonstrate that bicycle ergometry exhibits a distinct haemodynamic response with higher increase of PAWP compared to other modalities. This finding needs to be considered for valid detection of exercise PAWP ≥25 mmHg when non-bicycle tests remain inconclusive., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Multiple domains of quality of life (QoL) such as erectile function are not sufficiently investigated among left ventricular assist-device (LVAD) patients. We aimed to evaluate the prevalence of erectile dysfunction (ED) and its association with QoL and depression., Methods: This is a prospective, single-center, cross-sectional study. We included adult male LVAD patients who were clinically stable after at least 3 months post-implantation. Erectile function was assessed with the International Index of Erectile Function (IIEF-5) questionnaire with a score of ≤21 being confirmatory for ED. QoL and depression were estimated with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Patient Health Questionnaire depression scale (PHQ-8), respectively., Results: The study included 56 patients, of whom 45 (80 %) met criteria for ED, a prevalence much higher than previously reported in patients with established cardiovascular disease or conservatively treated heart failure. Patients with ED were older and had lower 6-minute walking distance. ED was not associated with comorbidities and heart failure medications but with less frequent use of diuretics and phosphodiesterase-5 inhibitors. There was a correlation between erectile function and depression as well as QoL., Conclusions: These findings underscore that ED deserves special attention and should be included in a multi-targeted approach to address suboptimal QoL outcomes after LVAD implantation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)

Alcohol septal ablation is an established treatment for selected patients with hypertrophic cardiomyopathy and left ventricular outflow tract obstruction (LVOT). The safety and efficacy of septal microsphere embolization (SME) have not been studied. We conducted a retrospective analysis of SME procedures performed at our center from 2006 to 2021 using 75-µm microspheres. The primary end point was LVOT gradient reduction. Secondary outcomes included periprocedural mortality, conduction disturbances, access site complications, and duration of hospitalization. The population comprised 76 patients (median age 61 years, men 43%). Dyspnea New York Heart Association ≥III was present in 65 patients (86%); ventricular tachycardia and previous syncope were described in 4% and 18%, respectively. Median duration of hospitalization was 13 days, and the time to first follow-up was 4 months. SME resulted in a significant reduction at rest (41 vs 12 mm Hg, mean Δ PG = -71%, p <0.001) and provoked LVOT gradients (94 vs 29 mm Hg, mean Δ PG = -75%, p <0.001). Periprocedural death occurred in 1 patient (1%) who underwent SME after transcatheter aortic valve replacement. Complete atrioventricular block was observed in 5 patients (7%). Left bundle branch block was diagnosed in 1 case (1%) and right bundle branch block in 3 (4%). Access site complications were observed in 4 patients (5%). In conclusion, SME is a safe and effective alternative to alcohol septal ablation. The potential advantages of microspheres are still to be investigated in prospective studies., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Phosphodiesterase-5 inhibitors (PDE5I) are frequently implemented after left ventricular assist device (LVAD) implantation to improve haemodynamics in patients with early postoperative right ventricular (RV) failure. It is unknown if long-term PED5I therapy beyond the early post-operative period provides any clinical benefit in stable outpatients, who have recovered from post-operative RV failure under univentricular device support. This study aimed to investigate the impact of PDE5I discontinuation on RV function and cardiopulmonary exercise capacity in patients on durable LVAD support., Methods and Results: We enrolled 31 clinically stable LVAD recipients on long-term oral PDE5I therapy. The mean age was 53 years, and 90% were male. Patients discontinued PDE5I and underwent cardiopulmonary exercise testing, echocardiography, LVAD interrogation, and biomarker analysis at baseline and 4 weeks after PDE5I withdrawal. At 4 weeks, no significant changes were observed in echocardiographic indices of RV morphology and function but an increase in peak tricuspid regurgitation velocity (2.1 vs. 2.4 m/s, P = 0.01). Peak oxygen consumption (11.4 vs. 11.8 mL/min/kg, P = 0.52), minute ventilation/carbon dioxide production slope (33 vs. 35, P = 0.56), N-terminal pro-brain natriuretic peptide (1455 vs. 1399 pg/mL, P = 0.55), flow and power readings of the device, and quality of life (Kansas City Cardiomyopathy Questionnaire score 78.3% vs. 77.5%, P = 0.62) exhibited no significant changes. We observed an increase in 6-min walking distance (346 vs. 364 m, P = 0.03). Two patients were hospitalized for non-cardiac reasons (subtherapeutic INR, driveline infection). No patient was hospitalized for cardiac decompensation., Conclusions: In LVAD patients with a history of early post-operative RV failure, discontinuation of long-term PDE5I therapy was not associated with deterioration of RV function, exercise capacity, and quality of life. PDE5I should be critically evaluated until more evidence regarding the net clinical benefit of this pharmacologic intervention becomes available., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, but life-threatening protein misfolding disorder due to TTR gene mutations. Cardiomyopathy (ATTRv-CM) and polyneuropathy (ATTRv-PN) with early small nerve fibre involvement are the most common manifestations. Timely diagnosis and treatment initiation are key to limiting progression of disease. Corneal confocal microscopy (CCM) is a non-invasive method to quantify corneal small nerve fibres and immune cell infiltrates in vivo., Methods: This cross-sectional study investigated the utility of CCM in 20 patients with ATTRv amyloidosis (ATTRv-CM, n = 6; ATTRv-PN, n = 14) and presymptomatic carriers (n = 5) compared to 20 age- and sex-matched healthy controls. Corneal nerve fibre density, corneal nerve fibre length, corneal nerve branch density, and cell infiltrates were assessed., Results: Corneal nerve fibre density and nerve fibre length were significantly lower in patients with ATTRv amyloidosis compared to healthy controls regardless of the clinical phenotype (ATTRv-CM, ATTRv-PN) and corneal nerve fibre density was significantly lower in presymptomatic carriers. Immune cell infiltrates were only evident in patients with ATTRv amyloidosis, which correlated with reduced corneal nerve fibre density., Conclusions: CCM identifies small nerve fibre damage in presymptomatic carriers and symptomatic patients with ATTRv amyloidosis and may serve as a predictive surrogate marker to identify individuals at risk of developing symptomatic amyloidosis. Furthermore, increased corneal cell infiltration suggests an immune-mediated mechanism in the pathogenesis of amyloid neuropathy., (© 2023. The Author(s).)

Cardiac transthyretin amyloidosis is an infiltrative cardiomyopathy with high mortality. To date, there are no specific biomarkers to directly assess disease activity and response to specific treatments. Our aim was to evaluate scintigraphic changes after treatment with the transthyretin stabilizer tafamidis. Methods: We included patients who had undergone 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ( 99m Tc-DPD) scintigraphy before tafamidis initiation and after at least 9 mo. Tracer activity was assessed visually and quantitatively as SUV max Results: The study included 14 patients who were on tafamidis for 44 ± 14 mo. We observed regression of Perugini grade in 5 patients, unchanged grade in 9 patients, and regression of mean heart-to-contralateral-lung ratio ( P = 0.015) and SUV max ( P = 0.005). There were no changes in N-terminal pro-B-type natriuretic peptide or echocardiographic measures. Conclusion: Treatment with tafamidis results in regression of myocardial 99m Tc-DPD uptake. 99m Tc-DPD scintigraphy may provide useful imaging biomarkers to assess response to treatment., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Plantar fasciitis is a common cause of heel pain. The aim of this study was to review the current literature and attempt to clarify whether endoscopic plantar fasciotomy (EPF) is an effective and reliable treatment for plantar fasciitis in comparison with other invasive or noninvasive treatments. We performed an electronic search of the medical literature in PubMed database using combinations of the following keywords: plantar fasciitis, endoscopic treatment, and plantar aponeurosis. Overall, we had shown that patients had better scores following EPF/endoscopic plantar fascia release. The clinical scores were improved postoperatively and most of the patients were satisfied. Furthermore, the clinical trials showed that time to return to work or to previous activities was shorter compared with other treatments. These studies suggest that EPF/endoscopic plantar fascia release is probably an effective treatment of chronic plantar fasciitis. EPF is an efficient, safe treatment with good early postoperative results in patients with recalcitrant plantar fasciitis. There is evidence that other methods are equivalently effective for EPF, and some authors support that they should be considered as a second-line treatment because of their minimal invasive character and very low risk of complications; thus, more research is required.

Introduction: Organ shortage, subsequent use of extended donor criteria organs and high-risk recipients needing redo-surgery are increasing the complexity of heart transplantation. Donor organ machine perfusion (MP) is an emerging technology allowing reduction of ischemia time as well as standardized evaluation of the organ. The aim of this study was to review the introduction of MP and analyze the results of heart transplantation after MP in our center., Methods: In a retrospective single-center study, data from a prospectively collected database were analysed. From July 2018 to August 2021, fourteen hearts were retrieved and perfused using the Organ Care System (OCS), 12 hearts were transplanted. Criteria to use the OCS were based on donor/recipient characteristics. Primary objective was 30-day survival, secondary objectives were major cardiac adverse events, graft function, rejection episodes as well as overall survival in the follow-up and assessment of MP technical reliability., Results: All patients survived the procedure and the postoperative 30-day interval. No MP related complications were noted. Graft ejection fraction beyond 14 days was ≥ 50% in all cases. Endomyocardial biopsy showed excellent results with no or mild rejection. Two donor hearts were rejected after OCS perfusion and evaluation., Conclusion: Ex vivo normothermic MP during organ procurement is a safe and promising technique to expand the donor pool. Reduction of cold ischemic time while providing additional donor heart assessment and reconditioning options increased the number of acceptable donor hearts. Additional clinical trials are necessary to develop guidelines regarding the application of MP., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Diagnosis and treatment of heart failure (HF) is challenging, and development of specialized HF networks is mandatory to warrant broad access to guideline directed therapies for patients. Numerous national cardiovascular societies recommend a three-level association of health care providers. This comprises tertiary academic centres, specialized HF clinics and specialized general cardiologists to cover the large spectrum of HF severity and entities. Although this idea of a multi-level care is widely accepted, optimal approach to build and implement a HF network service needs further definition. The core principle is that of network healthcare facilities that also consider regional peculiarities and that implements academic standards, quality indicators (QIs), interdisciplinarity and reimbursement strategies. These determinants of trans-sectoral healthcare need to be embedded in a network that provides sustainability and that incorporates QIs to objectify the efficacy of specific measures. The basis of a HF-network should be a certification system of the respective national HF association to warrant guideline standards and to prevent development of regional hierarchies or dependencies between members. This nationwide framework needs to be complemented by a federal system of regional networks, which also takes local demands into account. These regional units should incorporate digital communication and interaction pathways, structured educational programmes, certified telehealth concepts and follow-up algorithms to meet the requirements of sustainability and efficacy. We here summarize different components of HF networks and introduce the structure and development philosophy of the RUHR-HF-network that constitutes the first certified HF-clinics-network in the Ruhr area-the largest metropolitan area in Germany., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Extra Corporeal Life Support (ECLS) is an evolving therapy in therapy-resistant cardiogenic shock (CS). Vascular cannulation in emergency situations can be accomplished through puncture of the femoral vessels by specialised teams. Since lower limb ischemia constitutes one of the major complications following cannulation, a distal perfusion cannula (DPC) has emerged as standard of care. We here aimed to analyse the impact of the DPC on limb perfusion and 6-month survival rate., Methods: In a retrospective study from January 2012 to December 2018, 98 patients with cardiogenic shock and peripheral (v-a) ECLS implantation with documented limb perfusion status were identified and analysed. Demographic data, laboratory parameters, cause of CS, comorbidities, limb perfusion complications and complication management were analysed., Results: 53 patients (54%) received ECLS therapy in referral centers by our mobile ECLS team, while in 45 patients (46%) the cannulation occured in our center. 71 patients (72%) received a DPC (group A) at the time of ECLS implantation, whereas 27 (28%) (group B) did not or received later (14 patients owing to limb ischemia). 44 patients (45%) developed limb ischemia as a complication of ECLS therapy (31% in group A and 81% in group B- p < 0.001). The 6-month survival rate was 28% in our study cohort (30% in group A and 22% in group B- p = 0.469)., Conclusion: Lower limb ischemia remains a serious complication after peripheral ECLS cannulation in CS, especially when a DPC is absent. Standardised DPC implementation may reduce the rate of severe limb complications in peripheral ECLS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background: High-intensity interval training (HIIT) of 4 minutes at 80%-90% of peak oxygen consumption (VO 2peak ) has been shown to be feasible in patients with left ventricular assist devices (LVADs). The effect of shorter bouts of HIIT, which reduce the anaerobic burden, has not been investigated compared to moderate continuous training (MCT)., Methods and Results: We conducted a prospective, monocentric study (NCT05121077) randomizing patients with LVADs into 20 minutes of MCT (n = 10) or short bouts (≤ 90 seconds) of HIIT (n = 10) following cardiopulmonary exercise testing at 50%-60% and 80%-90% of VO 2peak . Each of the 18 supervised sessions (3×/week, t 0- t 1 ) included 10 minutes of strengthening training. The primary outcome was the increase of VO 2peak in the 2 groups between t 0 and t 1 . Secondary outcomes were changes in the 12-item Kansas City Cardiomyopathy Questionnaire, the 6-minute walk distance and the percentage of VO 2peak at the first ventilatory threshold. VO 2peak significantly increased with HIIT (13.0 ± 4.6mL/kg/min vs 14.6 ± 4.3mL/kg/min; P = 0.037), but not with MCT (11.8 ± 3.3mL/kg/min vs 13.1 ± 3.3mL/kg/min; P = 0.322), without between-group differences (P = 0.853). Secondary outcomes improved from t 0- t 1 in MCT and HIIT, without differences between the groups., Conclusions: Short bouts of HIIT are feasible, and they improved VO 2peak and functional parameters in patients in this pilot prospective study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We evaluated the efficacy and prognostic impact of bortezomib-lenalidomide triplet (VRd) or daratumumab-based quadruplets (DBQ) versus previous anti-myeloma therapies, that is, bortezomib standard combinations (BSC) or conventional chemotherapy (CT), in a large cohort of patients with primary plasma cell leukemia (pPCL), including those fulfilling the revised diagnostic criteria, that is, circulating plasma cells (cPCS): ≥5%; 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44-86) out of 3324 myeloma patients (3%), registered in our database between 2001 and 2021, were studied; 37% had cPCS 5%-19%; 89% received novel combinations including DBQ (21%), VRd (16%) and BSC (52%); 35% underwent autologous stem cell transplantation. 83% achieved objective responses. Treatment with VRd/DBQ strongly correlated with a higher complete response rate (41% vs. 17%; p = .008). After a median follow-up of 51 months (95% CI: 45-56), 67 patients died. Early mortality was 3.5%. Progression-free survival was 16 months (95% CI: 12-19.8), significantly longer in patients treated with VRd/DBQ versus BSC/CT (25 months, 95% CI: 13.5-36.5 vs. 13 months 95% CI: 9-16.8; p = .03). Median overall survival (OS) was 29 months (95% CI: 19.6-38.3), significantly longer in patients treated with VRd/DBQ versus BSC/CT (not reached vs. 20 months, 95% CI: 14-26; 3-year OS: 70% vs. 32%, respectively; p < .001; HzR: 3.88). In the multivariate analysis VRd/DBQ therapy, del17p(+) and PLT <100.000/μL, independently predicted OS (p < .05). Our study has demonstrated that in the real-world setting, treatment with VRd/DBQ induces deep and durable responses and is a strong prognostic factor for OS representing currently the best therapeutic option for pPCL., (© 2023 Wiley Periodicals LLC.)

(1) Background: The transcoronary ablation of septal hypertrophy (TASH) is an established therapy for hypertrophic obstructive cardiomyopathy (HOCM). Previous studies on this topic are characterised by a consistent male predominance and show a worse prognosis in females. (2) Methods: This study is a retrospective analysis of all TASH procedures conducted between 2006 and 2021 at a tertiary academic centre. A solution of 75 µm microspheres (Embozene ® , Boston Scientific, Marlborough, MA, USA) was used as an embolising agent. The outcomes of interest were left ventricular outflow tract (LVOT) gradient reduction and symptom improvement among males vs. that among females. Secondarily, we analysed the sex-related differences in procedural safety outcomes and mortality. (3) Results: The study population consisted of 76 patients, with a median age of 61 years. Females comprised 57% of the cohort. We observed no sex-related differences in the baseline LVOT gradients at rest or under provocation ( p = 0.560 and p = 0.208, respectively). Females were significantly older at the time of the procedure ( p < 0.001), had lower tricuspid annular systolic excursion (TAPSE) ( p = 0.009), presented a worse clinical status according to the NYHA functional classification (for NYHA ≥ 3, p < 0.001), and were more often on diuretics ( p < 0.001). We did not observe sex-related differences in absolute gradient reduction at rest ( p = 0.147) and under provocation ( p = 0.709). There was a reduction in the NYHA class by a median value of 1 ( p = 0.636) at follow-up for both sexes. Postprocedural access site complications were documented in four cases (two of which concerned females), and complete atrioventricular block was noted in five patients (three of which concerned females). The 10-year survival rates were comparable between the sexes (85% in females and 88% in males). The female sex was not associated with enhanced mortality according to multivariate analysis after adjusting for the confounding variables (HR 0.94; 95% CI 0.376-2.350; p = 0.895), but we observed age-related differences in long-term mortality (HR 1.035; 95% CI 1.007-1.063; p = 0.015). (4) Conclusions: TASH is safe and effective in both sexes, irrespective of their clinical differences. Women present at an advanced age and with more severe symptoms. An advanced age at the time of the intervention is an independent predictor of mortality.

Background: Percutaneous extracorporeal life support (pECLS) is increasingly applied in cardiogenic shock (CS) despite a lack of evidence from randomized trials. The in-hospital mortality rate of pECLS still reaches up to 60%, while vascular access site complications remain a shortcoming. Surgical approaches with central cannulation for ECLS (cELCS) have emerged as a bail-out option. To date, no systematic approach exists that allows a definition of inclusion or exclusion criteria for cECLS., Methods and Results: This single-center, retrospective, case-control study includes all patients fulfilling criteria for CS at the West German Heart and Vascular Center Essen/Germany between 2015 and 2020 who underwent cECLS ( n  = 58), excluding post-cardiotomy patients. Seventeen patients received cECLS (29.3%) as a first-line treatment strategy and 41 patients as a second-line strategy (70.7%). The main complications leading to the use of cECLS as a second-line strategy were limb ischemia (32.8%) and ongoing insufficient hemodynamic support (27.6%). The first-line cECLS cohort showed a 30-day mortality rate of 53.3% that was constant during follow-up. The 30-day mortality rate of secondary cECLS candidates was 69.8% and the rate at 3 and 6 months was 79.1%. Younger patients (<55 years) were more likely to exhibit survival benefit with cECLS ( p  = 0.043)., Conclusion: Surgical cECLS in CS is a feasible therapy for highly selected patients with hemodynamic instability, vascular complications, or peripheral access site limitations as complementary strategy in experienced centers., Competing Interests: BS acts as a remunerated proctor consultant for Abbott Inc., Abiomed GmbH, and Berlin heart GmbH, and the proctorship is not related to this study. FA-R received speaker honoraria, research honoraria, and consulting fees from Abiomed GmbH outside of the submitted work. TR received speaker honoraria and consulting fees from Astra Zeneca, Bayer, Pfizer, and Daiichi Sankyo. PL received speaker honoraria and consulting fees from Astra Zeneca, Bayer, Pfizer, and Edwards Lifesciences and research honoraria from Edwards Lifesciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Schmack, Schmack, Papathanasiou, Al-Rashid, Weymann, Pizanis, Kamler, Ruhparwar, Rassaf and Luedike.)

Background: Heart failure with preserved (HFpEF), mildly reduced (HFmrEF) and reduced (HFrEF) ejection fraction (EF) remains a controversial categorization. Whether these three categories reflect a distinct pattern of exercise limitation in cardiopulmonary exercise testing (CPET) needs to be investigated. We aimed to analyze whether CPET variables differ between all heart failure categories (HF)., Methods: We analyzed CPET variables of stable HFpEF (n = 123), HFmrEF (n = 31), and HFrEF (n = 153; 74 patients with and 79 patients without left ventricular assist device, LVAD) patients. The association between HF and peak oxygen consumption (VO 2peak ) was used as a primary outcome, while the association between HF, oxygen uptake efficiency slope (OUES), and increase of O 2 pulse (ΔO 2 pulse) were analyzed as secondary outcomes., Results: VO 2peak displayed a consistent decline across all HF categories (19.8 ml ± 6.2/kg/min vs. 17.5 ± 7.9 ml/kg/min vs. 13.7 ± 4.0 ml/kg/min, p < 0.001). OUES only showed differences between HFpEF and HFrEF (1.8 ± 0.6 vs. 1.4 ± 0.5, p < 0.001) as well as HFmrEF and HFrEF (1.9 ± 0.9 vs. 1.4 ± 0.5, p = 0.004). ΔO 2 pulse differed between HFpEF and HFrEF (7.7 ± 3.5 ml/beat/kg*100 vs. 5.5 ± 3.0 ml/beat/kg*100, p < 0.001) as well as HFpEF and HFmrEF (7.7 ± 3.5 ml/beat/kg*100 vs. 6.3 ± 4.1 ml/beat/kg*100, p = 0.049). Outcome variables did not differ between HFrEF with and without LVAD support (VO 2peak : p = 0.364, OUES: p = 0.129, ΔO 2 pulse: p = 0.564)., Conclusions: HF did not display a distinct CPET profile. Thus, EF-based categorization does not entirely reflect exercise limitations. CPET variables could contribute to better characterize HF phenotypes., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Cadmium-zinc-telluride (CZT)-based detectors exhibit higher diagnostic sensitivity in myocardial perfusion imaging (MPI) than conventional Anger-MPI for detection of coronary artery disease (CAD); however, reduced specificity and diagnostic accuracy of CZT-MPI were observed. This study aims to compare these different camera systems and to examine the degree of inter-rater reproducibility among readers with varying experience in MPI., Methods: 83 patients who underwent double stress/rest examinations using both a CZT and conventional SPECT cameras within one visit were included. Anonymized and randomized MPI-images were distributed to 15 international readers using a standardized questionnaire. Subsequent coronary angiography findings of ten patients served as a reference for analysis of sensitivity and specificity., Results: Image quality was significantly better in CZT-MPI with significantly lower breast attenuation (P < 0.05). CZT-MPI exhibited higher sensitivity than Anger-MPI (87.5% vs. 62.5%) and significantly reduced specificity (40% vs. 100%). Readers experienced with both camera systems had the highest inter-rater agreement indicating higher reproducibility (CZT 0.54 vs. conv. 0.49, P < 0.05)., Conclusions: Higher diagnostic sensitivity of CZT-MPI offers advantages in detection of CAD yet potentially of at the cost of reduced specificity, therefore it requires special training and a differentiated evaluation approach, especially for non-experienced readers with such camera systems., (© 2022. The Author(s).)

Beta-blocker (BB) therapy is a main pillar in treating patients with heart failure and reduced ejection fraction and has shown a prognostic benefit. However, evidence for application of BB in heart failure with preserved ejection fraction (HFpEF), especially in the absence of coronary artery disease, atrial fibrillation or arterial hypertension, is scarce. HFpEF is characterized by elevations in left atrial pressure and reduced compliance of the left ventricle leading to a hampered increase of cardiac output (CO) during exercise, which results in exertional dyspnea. This may be due to either a limited increase in stroke volume or reduced chronotropy during physical activity. We critically discuss the pathophysiological background of HFpEF, current data on BB in heart failure therapy, as well as the potential benefits and harms of BB therapy in HFpEF. Furthermore, we argue that non-cardio selective BB with peripheral activity to reduce afterload may be more suitable in this population than cardio-selective BB. Although preliminary data on BB in HFpEF are available, multicenter prospective trials to assess a reduction of cardiovascular morbidity are warranted. Future trials need to focus on phenotyping HFpEF patients and assess who may benefit most from tailored BB therapy., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Transthyretin (ATTR) amyloidosis is responsible for the majority of cardiac amyloidosis (CA) cases and can be reliably diagnosed with bone scintigraphy and the visual Perugini score. We aimed to implement a quantification method of cardiac amyloid deposits in patients with suspected cardiac amyloidosis and to compare performance to visual scoring., Methods and Materials: 136 patients received 99m Tc-DPD-bone scintigraphy including SPECT/CT of the thorax in case of suspicion of cardiac amyloidosis. Imaging phantom studies were performed to determine the scaling factor for standardized uptake value (SUV) quantification from SPECT/CT. Myocardial tracer uptake was quantified in a whole heart volume of interest., Results: Forty-five patients were diagnosed with CA. A strong relationship between cardiac SUVmax and Perugini score was found (Spearman r 0.75, p < 0.0001). Additionally, tracer uptake in bone decreased with increasing cardiac SUVmax and Perugini score (p < 0.0001). ROC analysis revealed good performance of the SUVmax for the detection of ATTR-CA with AUC of 0.96 ± 0.02 (p < 0.0001) with sensitivity 98.7% and specificity 87.2%., Conclusion: We demonstrate an accessible and accurate quantitative SPECT approach in CA. Quantitative assessment of the cardiac tracer uptake may improve diagnostic accuracy and risk classification. This method may enable monitoring and assessment of therapy response in patients with ATTR amyloidosis., (© 2022. The Author(s).)

Background: Beta blockers (BB) reduce chronotropic response and exercise capacity in heart failure with preserved ejection fraction (HFpEF). To analyze the influence of BB on exercise performance and O 2 pulse increase as a surrogate for stroke volume in HFpEF., Methods: We retrospectively analyzed the influence of BB intake (yes: n = 48/no: n = 51) on peak oxygen uptake (VO 2peak), oxygen uptake efficiency slope (OUES), and increase of O 2 pulse in HFpEF patients undergoing cardiopulmonary exercise testing (CPET). Associations of outcome variables and risk category of the algorithm of the Heart Failure Association of the European Society of Cardiology (HFA-PEFF score) were calculated., Results: Patients on BB showed lower VO 2peak (p = .003) and OUES (p = .002), with a dominant effect in the high-risk (p = .020; 0.002), but not in the low risk-group (p = .434; p = .499). In the intermediate group BB showed a trend towards lower VO 2peak (p = .078) and lower values for OUES (p = .020). Patients on BB also demonstrated a lower increase of O 2 pulse during exercise (p = .002), without differences between HFA-PEFF risk groups (low: p = .322, intermediate: p = .269, high: p = .313)., Conclusions: BB reduce exercise capacity and O 2 pulse increase in HFpEF patients. Direct quantification of O 2 pulse increase may help to improve the discrimination of HFpEF patients., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Exercise oscillatory ventilation (EOV), indicating pathological fluctuations on pulmonary arterial pressure, is associated with mortality in patients with heart failure (HF). Whether left ventricular assist device (LVAD)-induced ventricular unloading can reverse EOV and may prevent short-term rehospitalization has not been investigated., Methods: We performed a retrospective single-center in- and outpatient analysis of patients with (n = 20, LVAD) and without (n = 27, HF) circulatory support and reduced ejection fraction (EF, 22.8 ± 7.9%). The association of cardiopulmonary exercise testing (CPET) variables and 3 months-rehospitalization (3MR) as a primary outcome was analyzed. Furthermore, CPET variables were compared regarding the presence of EOV (+/-)., Results: Lower VO 2peak (11.6 ± 4.9 ml/kg/min vs. 14.4 ± 4.3 ml/kg/min, p = 0.039), lower increase of PETCO 2 (CI = 0.049-1.127; p = 0.068), and higher VE/VCO 2 (43.8 ± 9.5 vs. 38.3 ± 10.6; p = 0.069) were associated with 3MR. Flattening of O 2 pulse (CI = 0.139-2.379; p = 0.487) had no impact on 3MR. EOV was present in 59.5% (n = 28/47) of patients, without a significant difference between LVAD and HF patients (p = 0.959). Patients with HF/EOV+ demonstrated significantly lower VO 2peak compared with HF/EOV- (p = 0.039). LVAD/EOV+ displayed significantly lower EF (p = 0.004) and fewer aortic valve opening than LVAD/EOV- (p = 0.027)., Conclusions: Lower VO 2peak , but not EOV, was associated with 3MR. EOV occurred at a similar rate in LVAD and HF patients, which may illustrate insufficient unloading during exercise in chronic LVAD therapy and may contribute to the limited exercise capacity following LVAD implantation. Simultaneous CPET and right heart catheterization studies are needed to elucidate whether EOV may serve as a non-invasive predictor of insufficient LV unloading necessitating LVAD reprograming., (© 2022 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: Hereditary transthyretin (ATTRv) amyloidosis is a rare, genetically heterogeneous and phenotypically variable systemic disease characterized by deposition of misfolded transthyretin fibrils in various tissues. ATTRv cardiomyopathy and progressive axonal polyneuropathy are the most common manifestations, leading to severe disability and ultimately death within approximately ten years. As disease-modifying treatment options evolve, timely diagnosis and treatment initiation are crucial to prevent rapid disease progression., Case Presentation: Here, we report on a 73-year old patient initially diagnosed with cardiac wild-type ATTR (ATTRwt) amyloidosis by endomyocardial biopsy. Molecular genetic analysis revealed a novel TTR sequence variant (p.Ala65Val) that is highly likely to be amyloidogenic in light of previously reported TTR mutations and the patient's clinical presentation and family history., Conclusions: Our findings expand the spectrum of known pathogenic TTR mutations and underline the importance of a thorough diagnostic workup in amyloidosis patients including careful genetic testing to avoid misdiagnosis and missing of treatment opportunities and to enable cascade testing and tracking of carriers., (© 2022. The Author(s).)

Opposing acute lymphoblastic leukemia, sparse data about AYAs with acute myeloid leukemia (AML) is available. Overall, 125 AYAs (age 10-35 years) treated during the last two decades were evaluated and compared to 385 older patients. CBF leukemia was more frequent in AYAs (21.6% vs. 8%, p  < 0.001); however, many presented high-risk features. AYAs showed improved complete remission rate (CR, 80% vs. 65%, p  = 0.01), lower cumulative incidence of relapse and TRM and longer survival (5 year-OS 53% vs. 24%, p  < 0.0001), observed mainly in intermediate-risk karyotype. Adolescents displayed even better outcomes (5 year-OS 69%). AlloHCT in CR1 was beneficial for nonadolescent AYAs (5 year-OS 66.7% vs. 44.4% without HCT, p  = 0.04). Among 50 APL patients, 19 AYAs experienced better outcomes than older, mainly attributed to reduced treatment-related mortality (TRM, 5% vs. 19%, p  = 0.1). We observed an important (>10%) survival gain for AYAs during the last decade. However, AYAs have still unmet needs to obtain optimal cure rates.

Bone marrow failure (BMF) syndromes are a group of various hematological diseases with cytopenia as a main common characteristic. Given their rarity and continuous progress in the field, we aim to provide data considering the efficiency and safety of the therapeutic methods, focusing on the treatment of aplastic anemia(AA) and paroxysmal nocturnal hemoglobinuria (PNH). We enrolled consecutive patients diagnosed with BMF in two referral centers of Northern Greece from 2008 to 2020. We studied 43 patients with AA (37 adults and 6 children/adolescents) and 6 with classical PNH. Regarding classical PNH, 4 patients have received eculizumab treatment with 1/4 presenting extravascular hemolysis. Among 43 patients with aplastic anemia, PNH clones were detected in 11. Regarding patients that did not receive alloHCT (n=15), 14/15 were treated with ATG and cyclosporine as first line, with the addition of eltrombopag in patients treated after its approval (n=9). With a median follow-up of 16.7 (1.8-56.2) months from diagnosis, 12/14 (85.7%) are alive (4-year OS: 85.1%). AlloHCT was performed in 28 patients. Five patients developed TA-TMA which did not resolve in 3/5 (all with a pre-transplant PNH clone). With the follow-up among survivors reaching 86.3 (6.3-262.4) months, 10-year OS was 56.9%, independently associated with PNH clones after adjusting for age (p=0.024). In conclusion, our real-world experience confirms that novel treatments are changing the field of BMF syndromes. Nevertheless, there is still an unmet need to personalize algorithms in this field., Competing Interests: EG has received honoraria from Alexion and Omeros Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gavriilaki, Tragiannidis, Papathanasiou, Besikli, Karvouni, Douka, Paphianou, Hatzipantelis, Papaioannou, Athanasiadou, Marvaki, Panteliadou, Vardi, Batsis, Syrigou, Mallouri, Lalayanni and Sakellari.)

Introduction: Immunoglobulin light chain (AL) amyloidosis is a life-threatening systemic disease due to plasma cell dyscrasias, which is characterized by amyloid deposition in various tissues. Neurological manifestations, in particular peripheral nervous system involvement, play a major role for quality of life and treatment decisions as frequently potentially neurotoxic drugs are used., Methods: We retrospectively investigated the prevalence of neurological manifestations, its risk factors and prognostic value in 155 consecutive patients with AL amyloidosis in a single German tertiary center between 2010 and 2021. Multiple logistic regression was performed to identify predictors of amyloid neuropathy and the impact of peripheral neuropathy on patient survival was assessed by Cox proportional hazard regression analysis., Results: Nearly half of patients showed at least one of four neurological manifestations of AL amyloidosis which were frequent in our study: peripheral neuropathy (36.8%), carpal tunnel syndrome (12.9%), lumbar spinal stenosis (7.1%), and amyloid myopathy (3.9%). Male sex (OR 2.943, CI 1.152-8.139, p = 0.029) and cardiac involvement (OR 6.186, CI 1.449-43.38, p = 0.028) were independent predictors of peripheral neuropathy which was closely related to autonomic dysfunction in patients with AL amyloidosis. Peripheral neuropathy had no impact on survival (HR 0.952, CI 0.517-1.754, p = 0.876)., Conclusions: Neurological involvement is common in systemic AL amyloidosis. Treatment decisions should take into account peripheral neuropathy, in particular in male patients with amyloid cardiomyopathy, but also amyloid myopathy that seems to be not as rare as previously suggested., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Light chain (AL) amyloidosis is a life-threatening disorder characterised by extracellular deposition of amyloid leading to dysfunction of multiple organs. Peripheral nerve involvement, particularly small fibre neuropathy, may be associated with poorer survival. Corneal confocal microscopy (CCM) is a rapid and non-invasive imaging technique to quantify corneal small nerve fibres and immune cells in vivo. We aimed to evaluate CCM as a tool for early diagnosis of peripheral nerve involvement in AL amyloidosis., Methods: CCM and nerve conduction studies (NCS) were undertaken in 21 newly diagnosed, treatment-naïve AL amyloidosis patients and 21 age- and sex-matched healthy controls. Corneal nerve fibre density (CNFD), corneal nerve branch density and fibre length, and cell infiltrates were quantified in the sub-basal layer of the cornea., Results: There was a significant reduction in CNFD and nerve fibre length, even without large fibre affection and an increase in cell density, particularly around corneal nerve fibres in patients with AL amyloidosis compared to controls. Additionally, cell infiltration correlated with reduced nerve fibre density in patients with AL amyloidosis, but reduced CNFD did not correlate with laboratory parameters of organ dysfunction., Interpretation: Our study is the first to show that CCM allows rapid non-invasive identification of early small nerve fibre damage associated with immune cell infiltration in patients with AL amyloidosis. CCM detects peripheral nerve involvement more sensitively than NCS., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Aims: The study aimed to investigate the prevalence, phenotypic characteristics, and predictors of atrial fibrillation (AF) in patients presenting with cardiac amyloidosis (CA) of light-chain (AL) or transthyretin (ATTR) type., Methods and Results: Clinical, biochemical, and echocardiographic data of patients presenting with CA between 2005 and 2020 were retrospectively collected. CA staging was based on established biomarker systems. Binomial logistic regression was run to analyse the effects of clinical variables on the likelihood of AF. The study included 133 patients [53% AL, 41% wild-type (wt) ATTR-CA, & 6% hereditary ATTR-CA]. Mean age was 71 years, and 80% were male patients. AF was diagnosed in 64 (48%) patients (28% in AL-CA, 80% in wtATTR, 13% in hATTR, P < 0.001). Patients with AF were older (74 vs. 69 years, P < 0.001), more likely to have wtATTR-CA (67 vs. 16%, P < 0.001), exhibited more often New York Heart Association ≥ III symptoms (66 vs. 45%, P = 0.02) and carried a higher burden of comorbidities. AF patients had lower left ventricular ejection fraction (47 vs. 53%, P < 0.005), higher left atrial volume index (54 vs. 46 mL/m 2 , P = 0.007), higher pulmonary artery pressure (42 vs. 31 mmHg, P = 0.008), and worse tricuspid annular plane systolic excursion values (17 vs. 20 mm, P = 0.01). Mitral regurgitation ≥ Grade 2 was more frequent in AF (56 vs. 25%, P < 0.001). Higher ATTR-CA stage was associated with higher AF prevalence (47% vs. 74% vs. 94%, P < 0.001, for Stages I, II, & III, respectively). Higher AL-CA stage was associated with lower AF prevalence (0% vs. 40% vs. 31% vs. 18%, P < 0.001, for Stages I, II, IIIa, & IIIb, respectively). Three independent predictors for AF were identified in a multivariate logistic regression model with 81.5% classification accuracy: AL type [odds ratio (OR) 0.1, confidence interval (CI) 0.01-0.29, P = 0.001], estimated glomerular filtration rate (OR 0.9, CI 0.93-0.99, P = 0.03), and body mass index (OR 1.3, CI 1.07-1.66, P = 0.01). ATTR amyloidosis was associated with a 10-fold higher risk of AF. During 1 year follow-up, only one episode of ischaemic stroke was reported., Conclusions: Atrial fibrillation affects nearly half of all patients with CA. Patients presenting with AF have more severe symptoms and higher burden of comorbidities. ATTR type of amyloidosis is the strongest predictor of AF. Prospective screening for occult AF may be considered in ATTR-CA., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The demyelinating syndromes of the central nervous system (CNS) that occur in the context of systemic lupus erythematosus (SLE) may represent a manifestation of neuropsychiatric lupus (NPSLE) or an overlap of SLE and multiple sclerosis (MS). The differential diagnosis between the two entities has important clinical implications because the therapeutic management differs., Objectives: To characterize CNS demyelinating syndromes in a large SLE cohort as neuropsychiatric SLE (NPSLE) or SLE-MS overlap using a multidisciplinary approach and existing diagnostic (for MS) and classification criteria (for SLE)., Methods: Patients from the "Attikon" lupus cohort ( n = 707) were evaluated for demyelinating syndromes. Clinical, laboratory, and neuroimaging data were recorded for each patient. Following multidisciplinary evaluation and application of criteria, the demyelinating syndrome was attributed to either SLE or MS. Patients with transverse myelitis were not included in this study., Results: We identified 26 patients with demyelinating syndromes (3.7%). Of them, 12 were diagnosed as primary SLE-demyelination (46.2%) and 14 as overlap SLE-MS (53.8%). The two groups did not differ with respect to rheumatologic and neurologic manifestations or autoantibodies. SLE patients with demyelination manifested mild extra-CNS disease mainly involving joints and skin, while severe non-CNS manifestations were rare. However, these patients were less likely to have elevated IgG index (OR 0.055 95% CI: 0.008-0.40) and positive oligoclonal bands (OR 0.09 95% CI: 0.014-0.56), as well as brain lesions in the spinal cord, infratentorial, periventricular, and juxtacortical regions. A single brain region was affected in 9 patients with SLE-demyelination (75%), while all patients with MS-SLE had multiple affected brain regions. MS-SLE overlap was associated with an increased likelihood of neurologic relapses (OR 18.2, 95% CI: 1.76-188), while SLE-demyelination patients were less likely to exhibit neurological deficits (EDSS >0) at the last follow-up visit (50 vs. 78.6% in SLE-MS, respectively)., Conclusions: Demyelination in the context of SLE follows a more benign course compared to a frank SLE-MS overlap. Extension of follow-up will ascertain whether patients with SLE-demyelination evolve to MS, or this is a bona fide NPSLE syndrome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nikolopoulos, Kitsos, Papathanasiou, Kapsala, Garantziotis, Pieta, Gioti, Grivas, Voumvourakis, Boumpas and Fanouriakis.)

Background: Mitral valve regurgitation (MR) is a common finding in patients with end-stage heart failure. The aim of the study was to analyze the impact of preoperative moderate-to-severe MR on postoperative outcomes and survival after durable left-ventricular assist device (LVAD) implantation., Methods: From August 2010 to May 2021, 246 patients underwent a durable LVAD implantation. We stratified the patients into two groups: Group A (n = 109) presented with MR 0-I°, and Group B presented with MR II-III° (n = 137). MR II-III° was defined according to the current recommendations (i.e., vena contracta ≥ 7 mm, regurgitation volume ≥ 30 ml or effective regurgitation orifice area ≥ 20 mm 2 )., Results: Significantly more patients in Group B suffered from pulmonary hypertension and presented with chronic obstructive lung disease. We observed significantly higher rates of tricuspid regurgitation (TR) II-III° in Group B (76.1%) versus Group A (14.8%) (p < 0.001) and TR III° in Group B (30.4%) versus Group A (3.7%) (p < 0.001). There was no difference in the incidence of right heart failure between the groups. Within our cohort, the in-hospital, 1-year, 3-year, and 5-year mortality was 22.4%, 32.1%, 50.7%, and 64.4%, respectively. Group B showed significantly worse overall survival (p = 0.05). Patients with preoperative TR II-III° had a significantly worse survival than those with TR 0-I° (p = 0.048). In patients presenting with MR II-III°, we discovered that TR III° seems to predict both in-hospital and mid-term mortality., Conclusion: MR II-III° negatively affects the outcomes in patients requiring LVAD implantation. Persisting MR II-III° is an independent predictor of mortality. Patients with concomitant preoperative TR II-III° are at increased risk of developing postoperative major adverse events. Addressing the MR might be considered for these patients., (© 2021 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Previous sMRI, DTI and rs-fMRI studies in small cell lung cancer (SCLC) patients have reported that patients after chemotherapy had gray and white matter structural alterations along with functional deficits. Nonetheless, few are known regarding the potential alterations in the topological organization of the WM structural network in SCLC patients after chemotherapy. In this context, the scope of the present study is to evaluate the WM structural network of 20 SCLC patients after chemotherapy and to 14 healthy controls, by applying a combination of DTI with graph theory. The results revealed that both SCLC and healthy controls groups demonstrated small world properties. The SCLC patients had decreased values in the clustering coefficient, local efficiency and degree metrics as well as increased shortest path length when compared to the healthy controls. Moreover, the two groups reported different topological reorganization of hub distribution. Lastly, the SCLC patients exhibited significantly decreased structural connectivity in comparison to the healthy group. These results underline that the topological organization of the WM structural network in SCLC patients was disrupted and hence constitute new vital information regarding the effects that chemotherapy and cancer may have in the patients' brain at network level., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The ideal timing of a durable assist device implantation in patients with end-stage heart failure presenting with INTERMACS profile I is still controversial. The data on extracorporeal life support (ECLS) bridge to durable left ventricular assist device (LVAD) in these patients is limited., Materials and Methods: We retrospectively analyzed the outcomes of 35 patients in acute cardiogenic shock (CS) who, between December 2013 and September 2020, were bridged with ECLS to durable LVAD. The mean age was 52.3 ± 12.0 years. The primary endpoints of this study were in-hospital, 30-day, 6-month, and 1-year mortality. The secondary endpoint was the development of any postoperative adverse events and other characteristics during the follow-up period. We also assessed the impact of the rescue ECLS on the recovery of the end-organ function., Results: In-hospital, 30-day, 6-month, and 1-year survival was 65.6%, 75.9%, 69.2%, and 62.7% respectively. The median time on ECLS was 7 days (IQR 5.0-13.0). We observed a high incidence of a severe right heart failure (22.9%), acute kidney injury on dialysis (68.6%), and respiratory failure (77.1%). Bridge with ECLS provided a significant recovery of liver and kidney function prior to durable LVAD implantation., Conclusion: The concept of bridging patients presenting in end-stage heart failure and cardiogenic shock with ECLS prior to durable LVAD implantation is a feasible method to ensure acceptable survival rates and significant recovery of the end-organ function.

Therapy related acute myeloid leukemia (tAML) and secondary AML after an antecedent hematologic disorder (sAML-AHD) are often addressed together, blurring any clinical and prognostic differences. Among 516 AML patients, we compared characteristics and outcomes of 149 patients with "sAML" (sAML-AHD: 104, tAML: 45), uniformly and intensively treated during the last 2 decades at 1 center. Clinical outcomes of the whole "sAML" cohort were significantly inferior compared to de novo AML and in both intermediate and poor cytogenetic risk groups. Adverse karyotype had no effect on survival in tAML, while it was a negative predictor in sAML-AHD. Both groups showed similarly dismal outcome, with low complete remission rates (CR 44% vs. 41%) and median overall survival (OS 7 vs. 10.5 months). Allogeneic hematopoietic cell transplantation (alloHCT) recipients in CR1 had superior median OS (24 vs. 8 months). By multivariate analysis, alloHCT was an independent predictor of outcome, while karyotype was for sAML-AHD only. In conclusion, both "sAML" groups have inferior outcomes after chemotherapy, with adverse karyotype affecting primarily sAML-AHD. Until new treatment approaches are available, only alloHCT offers a survival advantage., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Bone-tracer scintigraphy has an established role in diagnosis of cardiac amyloidosis (CA) as it detects transthyretin amyloidosis (ATTR). Positron emission tomography (PET) with amyloid tracers has shown high sensitivity for detection of both ATTR and light-chain (AL) CA. We aimed to investigate the accuracy of 18 F-flutemetamol in CA., Methods: We enrolled patients with CA or non-amyloid heart failure (NA-HF), who underwent cardiac 18 F-flutemetamol PET/MRI or PET/CT. Myocardial and blood pool standardized tracer uptake values (SUV) were estimated. Late gadolinium enhancement (LGE) and T1 mapping/ extracellular volume (ECV) estimation were performed., Results: We included 17 patients (12 with CA, 5 with NA-HF). PET/MRI was conducted in 13 patients, while PET/CT was conducted in 4. LGE was detected in 8 of 9 CA patients. Global relaxation time and ECV were higher in CA (1448 vs. 1326, P = 0.02 and 58.9 vs. 33.7%, P = 0.006, respectively). Positive PET studies were demonstrated in 2 of 12 patients with CA (AL and ATTR). Maximal and mean SUV did not differ between groups (2.21 vs. 1.69, P = 0.18 and 1.73 vs. 1.30, P = 0.13)., Conclusion: Although protein-independent binding is supported by our results, the diagnostic yield of PET was low. We demonstrate here for the first time the low sensitivity of PET for CA., (© 2020. The Author(s).)

Background: Differences have been noted in the clinical presentation and mutational spectrum of CADASIL among various geographical areas. The aim of the present study was to investigate the mode of clinical presentation and genetic mutations reported in Greece., Methods: After a systematic literature search, we performed a pooled analysis of all published CADASIL cases from Greece., Results: We identified 14 studies that reported data from 14 families comprising 54 patients. Migraine with aura was reported in 39%, ischemic cerebrovascular diseases in 68%, behavioral-psychiatric symptoms in 47% and cognitive decline in 60% of the patients. The mean (±SD) age of onset for migraine with aura, ischemic cerebrovascular diseases, behavioral-psychiatric symptoms and cognitive decline was 26.2 ± 8.7, 49.3 ± 14.6, 47.9 ± 9.4 and 42.9 ± 10.3, respectively; the mean age at disease onset and death was 34.6 ± 12.1 and 60.2 ± 11.2 years. With respect to reported mutations, mutations in exon 4 were the most frequently reported (61.5% of all families), with the R169C mutation being the most common (30.8% of all families and 50% of exon 4 mutations), followed by R182C mutation (15.4% of all families and 25% of exon 4 mutations)., Conclusions: The clinical presentation of CADASIL in Greece is in accordance with the phenotype encountered in Caucasian populations, but differs from the Asian phenotype, which is characterized by a lower prevalence of migraine and psychiatric symptoms. The genotype of Greek CADASIL pedigrees is similar to that of British pedigrees, exhibiting a high prevalence of exon 4 mutations, but differs from Italian and Asian populations, where mutations in exon 11 are frequently encountered., (© 2021 European Academy of Neurology.)

Background and Aim: The synchronous occurrence of renal cell carcinoma and urothelial carcinoma of the renal pelvis in the same kidney is extremely rare, although previously reported. With this study we aim to present our case and provide a literature review on this entity., Methods: An otherwise healthy 43-year-old military male with the chief complaint of left plank pain was seen in the office. Imaging revealed the presence of a 3.5 cm left renal mass. Left laparoscopic radical nephrectomy was performed for presumed renal malignancy. Pathology confirmed the presence of a clear cell RCC and revealed an area of low-grade UC arising from the ipsilateral renal pelvis, not visible in the preoperative imaging. Furthermore, a Pubmed database search in English language was conducted, up to June 2021, to identify the rate of simultaneous RCC and UC of the renal pelvis or ureter in RN specimen performed for presumed RCC or renal malignancy and subsequent management in these cases., Results: A total of 53 articles reporting on 56 patients with synchronous ipsilateral RCC and UC of the renal pelvis were identified, together with our case. Eight cases (14%) were initially managed with RN, thereby requiring further management of the ureteral stump. Of these, six (75%) were managed with distal ureterectomy, one (12.5%) with active surveillance of the ureteral stump, while one case (12.5%) did not report subsequent management. To our knowledge, we present the youngest patient recorded in the literature, with this histology combination presenting synchronously in the same kidney., Conclusions: Although uncommon, the final pathology report may reveal neoplasms of dissimilar histology that may involve the renal pelvis. It is crucial for urologists and pathologists to be vigilant of such cases during a solid renal mass workup. Additional therapeutic adjustments may be necessitated, derailing the initial treatment plan.

Background: p.Ser43Asn is a very rare transthyretin (TTR) mutation leading to familial amyloidosis of transthyretin type, ATTR amyloidosis. It was previously observed in four patients worldwide and is associated almost invariably with an isolated cardiac phenotype., Methods and Results: We report here on an Italian family with early-onset cardiomyopathy and aggressive disease course in the affected individuals leading untreated to cardiac death before 55 years of age. We describe the clinical phenotype and imaging findings of two affected siblings, who were treated with tafamidis at an early disease stage, and their affected mother, who died 9 years ago due to refractory heart failure. The review of the available literature highlights the fact that until recently ATTR amyloidosis may have been misdiagnosed as other types of hypertrophic cardiomyopathy., Conclusion: A better characterization of the genotype-phenotype associations is crucial to achieve optimal outcomes and facilitate informed decisions when treating individuals with rare mutations., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

We have previously shown an advantage of a myeloablative conditioning regimen with reduced toxicity (Fludarabine 150 mg/m 2 , Treosulfan 42 g/m 2 , FluTreo) compared to a reduced-intensity regimen. We aimed to determine long-term safety and efficacy of FluTreo. We prospectively studied consecutive patients who received FluTreo in our center (2014-2019) on the basis of age (≥50 years), hematopoietic cell transplantation comorbidity index (HCT-CI) ≥2, or both. FluTreo recipients were then compared to a historical control group. We studied 68 FluTreo recipients, with a median age of 58.5 years and HCT-CI of 3. We calculated cumulative incidence (CI) of acute (grade 2-4) and moderate/severe chronic graft-versus-host disease (GVHD) (29.9% and 25%, respectively). The 3-year CI of treatment-related mortality was 19.1%, associated only with acute GVHD (P < .001). With a median follow-up of 27.3 (range 5.7-84.5) months in surviving patients, the 3-year overall survival (OS) was 56.6%, and disease-free survival (DFS) was 54.9%. Median survival has not yet been reached. Among pretransplantation and transplantation factors, only HCT-CI was associated with DFS and OS (P = .022 and P = .043, respectively). FluTreo recipients aged ≥50 with HCT-CI ≤ 2 had favorable DFS and OS compared with patients aged ≥50 with HCT-CI ≤2 after myeloablative conditioning. Our real-world study confirms that HCT with FluTreo expands the transplant population with favorable outcomes compared to previously used conditions. The choice of HCT in patients of a rather older age and comorbidity index needs to be revisited., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: To study the impact of time to diagnosis on cardiac Mayo stages, treatment outcome, and overall survival., Methods: We retrospectively analyzed 77 consecutive patients diagnosed between 2015 and 2020 with AL amyloidosis and cardiac involvement. Medical history was recorded in standardized form with the help of a questionnaire., Results: Time from onset of symptoms of cardiac failure to diagnosis was correlated with the severity of cardiac involvement in modified Mayo 2004 and revised Mayo 2012 staging systems (r s  = 0.30, 95% CI: 0.07-0.50, P = .007 and r s  = 0.25, 95% CI: 0.01-0.45, P = .03). Patients with advanced Mayo 2004 stages received reduced-intensity regimens and had a lower probability to achieve adequate hematologic- and cardiac response after first-line treatment than patients with early stages (r s  = 0.28, 95% CI: 0.04-0.48, P = .01 and r s  = 0.72, 95% CI: 0.55-0.82, P < .0001) and poorer overall survival (P = .0004). Compared with patients diagnosed within the first year, patients diagnosed after 13-18 or ≥19 months from first symptoms had a 3- to 5 times higher risk of dying. Our data indicate that there is a 12-month window within which the diagnosis of AL amyloidosis needs to be established to avoid early deterioration and death., Conclusions: Sensitizing physicians and raising awareness for the disease are crucial for timely diagnosis and may improve the outcome of the disease., (© 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Rapidly progressive dementia (RPD) is a clinical syndrome developing in <1 to 2 years. Recent progress in RPD evaluation is significant, so RPD's prevalence may change over time. The aim of our new case series was to estimate the relative frequency of RPDs' causative entities, considering the recent advances in RPDs' diagnosis, and compare the results with those of our previous report., Patients and Methods: We retrospectively reviewed the medical records of 47 patients who were referred to Attikon University Hospital during a 5-year period for a suspected RPD., Results: Neurodegenerative diseases were the most frequent causes (38%), followed by prion disease (19%) and autoimmune encephalopathy (AE, 17%). AE cases were by far more common than in our previous report, while other than AE secondary causes were significantly decreased. Mean time to dementia was 9 months in neurodegenerative diseases and 5 months in non-neurodegenerative. Main clinical findings across all patients were memory impairment (66%) and behavioral-emotional disturbances (48%)., Conclusions: Neurodegenerative diseases are common causes of RPD and have a slower evolution than non-neurodegenerative. Diagnostic novelties enabled the recognition of AE, whereas more common secondary causes are probably now diagnosed in primary settings since the recognition of RPD as distinct clinical entity is continually increasing., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)