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Abstract Background Subcellular trafficking is a hallmark of eukaryotic cells. Because of their pivotal role in the process, a great deal of attention has been paid to the SNARE proteins. Most R-SNAREs, or "longins", however, also possess a highly conserved, N-terminal fold. This "longin domain" is known to play multiple roles in regulating SNARE activity and targeting via interaction with other trafficking proteins. However, the diversity and complement of longins in eukaryotes is poorly understood. Results Our comparative genome survey identified a novel family of longin-related proteins, dubbed the "Phytolongins" because they are specific to land plants. Phytolongins share with longins the N-terminal longin domain and the C-terminal transmembrane domain; however, in the central region, the SNARE motif is replaced by a novel region. Phylogenetic analysis pinpoints the Phytolongins as a derivative of the plant specific VAMP72 longin sub-family and allows elucidation of Phytolongin evolution. Conclusion "Longins" have been defined as R-SNAREs composed of both a longin domain and a SNARE motif. However, expressed gene isoforms and splice variants of longins are examples of non-SNARE motif containing longins. The discovery of Phytolongins, a family of non-SNARE longin domain proteins, together with recent evidence on the conservation of the longin-like fold in proteins involved in both vesicle fusion (e.g. the Trs20 tether) and vesicle formation (e.g. σ and μ adaptin) highlight the importance of the longin-like domain in protein trafficking and suggest that it was one of the primordial building blocks of the eukaryotic membrane-trafficking machinery.

Abstract Background It is known that the orthographic properties of linguistic stimuli are processed within the left occipitotemporal cortex at about 150–200 ms. We recorded event-related potentials (ERPs) to words in standard or mirror orientation to investigate the role of visual word form in reading. Word inversion was performed to determine whether rotated words lose their linguistic properties. Methods About 1300 Italian words and legal pseudo-words were presented to 18 right-handed Italian students engaged in a letter detection task. EEG was recorded from 128 scalp sites. Results ERPs showed an early effect of word orientation at ~150 ms, with larger N1 amplitudes to rotated than to standard words. Low-resolution brain electromagnetic tomography (LORETA) revealed an increase in N1 to rotated words primarily in the right occipital lobe (BA 18), which may indicate an effect of stimulus familiarity. N1 was greater to target than to non-target letters at left lateral occipital sites, thus reflecting the first stage of orthographic processing. LORETA revealed a strong focus of activation for this effect in the left fusiform gyrus (BA 37), which is consistent with the so-called visual word form area (VWFA). Standard words (compared to pseudowords) elicited an enhancement of left occipito/temporal negativity at about 250–350 ms, followed by a larger anterior P3, a reduced frontal N400 and a huge late positivity. Lexical effects for rotated strings were delayed by about 100 ms at occipito/temporal sites, and were totally absent at later processing stages. This suggests the presence of implicit reading processes, which were pre-attentive and of perceptual nature for mirror strings. Conclusion The contrast between inverted and standard words did not lead to the identification of a purely linguistic brain region. This finding suggests some caveats in the interpretation of the inversion effect in subtractive paradigms.

Abstract Background Surgical treatment of hypopharyngeal cancers with extension to the retrocricoid region generally requires a circumferential pharyngolaryngectomy followed by a reconstruction of the removed segment of the upper digestive tract. Historically, many techniques have been used in order to achieve a safe and functional reconstruction. Jejunum interposition is generally considered the best reconstructive technique. Methods This study examines the details of the surgical technique, the complications, the oncological and the functional results in a series of 29 consecutive patients submitted to circumferential pharyngoesophageal resection for advanced hypopharyngeal cancer followed by reconstruction with a free flap of jejunum. Results Three of the transplants failed because of venous thrombosis. The overall success rate was 90%. There were no general complications. A good swallowing has been preserved in all our patients. All our patients where a phonatory prosthesis was positioned (20/29) were able to achieve speech following speech therapy and all were satisfied with their own capacity to communicate. Conclusions The prognosis of hypopharyngeal tumours (18–40% at 5 years) remains poor, but jejunum autografts are being shown to be an excellent choice for the reconstruction of the cervical hypopharyngo-oesophagus offering the patient fast rehabilitation and a reasonable quality of survival. Our experience confirm that this kind of reconstruction is safe with a good results in improving oncologic controls and restoring a good quality of life.

Background: Hypertension and exercise testing are essential for cardiovascular risk assessment. However, an exact description of blood pressure (BP) in patients with a hypertensive response during exercise (HRE), especially in the recovery phase is lacking. Herein, we aimed to analyse BP and heart rate during exercise testing and recovery in patients with an HRE., Methods: 800 patients aged 17-90 with an HRE during a standardized bicycle ergometry test were recruited. The BP behaviour during exercise testing was correlated with clinical data. Furthermore, data were analysed according to the presence of pre-existent hypertension., Results: Of the 800 patients included in this study 497 (62%) were previously diagnosed with hypertension. Analysis of covariance showed a significantly faster systolic (β [95% CI] 8.0 [4.9-11.1]) and diastolic (2.4 [0.4-4.4]) BP recovery 3 min after maximal exercise in patients without hypertension in univariable models. These results remained robust in fully adjusted models taking into account age, sex, body mass index, cardiovascular disease, and antihypertensive treatment for systolic (5.3 [1.2-9.4]) and diastolic BP (4.5 [1.9-7.0]). Furthermore, patients with hypertension displayed higher systolic BP during maximal exercise in univariable (3.8 [0.1-7.5]) and fully adjusted (5.5 [1.1-10.0]) models. There was no difference in maximum diastolic BP between groups., Conclusion: In this large cohort study, patients without hypertension showed a faster systolic and diastolic BP recovery and lower maximal systolic BP compared to patients with hypertension. Overall, this study provides new insights into cardiovascular health during recovery phase., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

A hypertensive response to exercise is a precursor leading to hypertension, which is a major risk factor for the development of heart failure and diastolic dysfunction. Herein, we aimed to assess blood pressure (BP) in patients with a hypertensive response to exercise and different degrees of diastolic dysfunction. Between January 2009 and December 2014, 373 patients with a hypertensive response to exercise (HRE) and echocardiographic data assessing diastolic function were enrolled at the University Hospital of Zurich. ANCOVA was used to assess the changes in BP response during exercise testing in individuals with different degrees of diastolic dysfunction. Normalization of systolic BP was blunted in patients with grade II and III diastolic dysfunction after 3 min of recovery in univariable [β (95%) - 9.2 (-13.8 to - 4.8) p < .001, -16.0 (-23.0 to 9.0) p < .001, respectively] and adjusted models. In fully adjusted models, when taking maximal effort into account, there were no differences with regard to systolic BP during exercise. Patients without diastolic dysfunction achieved higher heart rates (HRs) [both in absolute terms (p < .001) and as a percentage of the calculated maximum (p = .003)] and greater wattage (p < .001) at maximum exertion. The findings of this cross-sectional study suggest that exercise capacity is compromised in patients with diastolic dysfunction. A hypertensive response to exercise and the finding of a blunted BP recovery may help identify patients at risk of developing heart failure., (© 2024 The Author(s). The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: A significant proportion of patients with heart failure (HF) progress to an advanced stage, which is associated with a substantial increase in morbidity and mortality. These patients may be eligible for advanced treatment strategies such as mechanical circulatory support with ventricular assist devices (VAD). Vascular dysfunction is a hallmark of heart failure pathophysiology and prognosis. However, whether and to what degree the hemodynamic benefits of VADs influence vascular function remain unknown., Methods and Results: In this study, we evaluated endothelial vascular function with flow-mediated vasodilatation (FMD) and with flicker-light induced retinal vasodilatation (FID). 34 patients with a VAD (age 58 ± 10 years, 85% male, 74% ischemic heart disease, 26 continuous-flow (CF)-LVAD, and 8 pulsatile biventricular (bi)-VAD) were compared to 34 propensity-matched patients (mean age 62 ± 9 years, 68% male, 59% ischemic heart disease) with advanced HF (AdvHF). Endothelial function of larger arteries (FMD) was significantly better in patients after VAD implantation compared to matched AdvHF patients (7.2 ± 4.6% vs. 5.0 ± 3.2%, p = 0.03), whereas microvascular arteriolar function (FIDart) did not differ (0.99 ± 1.43% vs. 1.1 ± 1.7%, p = 0.78). The arterio-venous ratio (AVR) was higher in the VAD group (0.90 ± 0.06 vs 0.85 ± 0.09, p = 0.01), reflecting wider retinal arteriolar and narrower venular diameters. There was no difference in vascular function between patients with CF-LVAD and pulsatile Bi-VAD., Conclusion: In patients with advanced heart failure, VAD implantation was associated with better endothelial function at the level of large arteries, but not in the microcirculation., (© 2024. The Author(s).)

Background: Aortic diameters are related to age, sex, and body size. There is a scarcity of data on the long-term sequelae of a hypertensive response to exercise (HRE) on aortic diameters. In this retrospective cohort study, we aimed to evaluate the relationship between the growth rates of the aorta in individuals with a HRE., Methods: Our analysis included follow-up data of 649 patients recruited between January 2009 and December 2014 with a HRE. Participants with known connective tissue disease or a history of acute aortic syndrome were excluded. Sinus of Valsalva (SoV) and ascending aorta (AscAo) diameters were measured by transthoracic echocardiography using leading edge to leading edge convention at end-diastole., Results: At baseline, median age, maximum systolic blood pressure (BP), body mass index (BMI), diameter of the SoV, and AscAo were 62 years, 208 mm Hg, 26.9 kg/m2, 35 mm, and 35 mm respectively. 32% of patients were female and 67% had hypertension. After a median follow-up of 7.1 years, mean yearly growth rates (±SD) of the SoV and AscAo were 0.09 (0.41) mm and 0.13 (0.56) mm, respectively. No significant associations were observed between growth rates of aortic diameters and maximum systolic and diastolic BP or when considering only individuals with a baseline diameter >40 mm., Conclusions: In this large cohort study, maximum systolic and diastolic BP during exercise showed no association with growth rates of aortic diameters. Furthermore, the mean growth rates of aortic diameters in this population were in line with growth rates in a normal population., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, regardless of anaemia status. Iron supplementation has been demonstrated to improve exercise capacity and quality of life in patients with HF with an ejection fraction <50% and ID. This survey aimed to provide data on real-world practices related to ID screening and management., Methods and Results: We designed and distributed an online survey (23 questions) regarding ID screening and management in the HF setting. Overall, 256 cardiologists completed the survey (59.8% male, mostly between 30 and 50 years). The majority of physicians defined ID according to the most recent HF recommendations (98.4%) and reported screening for ID in more than half of their patients (68.4%). However, only 54.3% of the respondents performed periodic screening (every 6 months to 1 year). A total of 93.0% of participants prescribed and/or administered iron supplementation, using intravenous iron as the preferred method of administration (86.3%). After iron supplementation, 96.1% of the respondents reassessed ID, most frequently at 3-6 months (67.6%). Most physicians (93.8%) perceived ID as an underestimated comorbidity in HF. Cardiologists' age, training status, subspecialty and work setting (academic vs. non-academic hospitals) were associated with heterogeneity in the answers., Conclusions: The results of this survey highlight the need for more consistent strategies of ID screening and treatment for patients with HF., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Broad evidence indicates that hypertensive response to exercise (HRE) is associated with future hypertension (aHT) at rest and cardiovascular morbidity and mortality. Nevertheless, a consensus on the definition of HRE is lacking and the comparability of the available data is difficult due to a wide variation of definitions used. This review aims to harmonize currently available definitions of HRE in normotensive and athletic populations and to propose a generally valid cut-off applicable in everyday clinical practice. A literature search on PubMed and Embase was conducted to assemble and analyze the most recent data. Various definitions of HRE were identified and linked with future cardiovascular diseases. Forty-one studies defined HRE at a peak systolic blood pressure (SBP) above or equal to 200 mmHg in men and 25 studies for 190 mmHg in women. Peak diastolic blood pressure (DBP) between 90 and 110 mmHg was reported in 14 studies, relative DBP increase in four. Eight studies defined HRE as SBP between 160 and 200 mmHg at 100 watts. 17 studies performed submaximal exercise testing, while two more looked at BP during recovery. A plethora of other definitions was identified. In athletes, total workload and average blood pressure during exercise were considerably higher. Based on the presented data, the most commonly used definition of HRE at peak exercise is 210/105 mmHg for men, 190/105 mmHg for women, and 220/210 mmHg for athletes. Furthermore, a uniform exercise testing protocol, a position statement by leading experts to unify the definition of HRE, and prospective studies are warranted to confirm these cut-offs and the associated morbidity and mortality., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) results from a complex interplay of age, genetic, cardiac remodeling, and concomitant comorbidities including hypertension, obesity, diabetes, and chronic kidney disease (CKD). Renal failure is an important comorbidity of HFpEF, as well as a major pathophysiological mechanism for those patients at risk of developing HFpEF. Heart failure (HF) and CKD are intertwined conditions sharing common disease pathways; the so-called "kidney tamponade", explained by an increase in intracapsular pressure caused by fluid retention, is only the latest model to explain renal injury in HF. Recognizing the different phenotypes of HFpEF remains a real challenge; the pathophysiological mechanisms of renal dysfunction may differ across the HF spectrum, as well as the prognostic role. A better understanding of the role of cardiorenal interactions in patients with HF in terms of symptom status, disease progression, and prognosis remains essential in HF management. Historically, patients with HF and CKD have been scarcely represented in clinical trial populations. Current concerns affect the practical approach to HF treatment, and, in this context, physicians are frequently hesitant to prescribe and titrate both new and old treatments. Therefore, the extensive application of HF drugs in diverse HF subtypes with numerous comorbidities and different renal dysfunction etiologies remains a controversial matter of discussion. Numerous recently introduced drugs, such as sodium-glucose-linked transporter 2 inhibitors (SGLT2i), constitute a new therapeutic option for patients with HF and CKD. Because of their protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. The present review delves into the phenotype of patients with HFpEF and CKD from a pathophysiological perspective, proposing a treatment approach that suggests a practical stepwise algorithm for the proper application of life-saving therapies in clinical practice.

Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4-gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure., (© 2024. The Author(s).)

Background: Cardiovascular (CV) risk factors and CV diseases, in particular heart failure, are strongly associated with impaired microvascular retinal endothelial function. Whether atrial fibrillation (AF) contributes to vascular dysfunction is not clear. Therefore, the aim of this study was to investigate the impact of AF on retinal microvascular function., Methods: In this study, vascular function was measured non-invasively with flicker-light induced vasodilatation of retinal arterioles (FIDart%). Patients with a history of AF and risk factors for heart failure (HF) or heart failure (n = 69; age 67.9 ± 9.2 years, 71% male, 35% HFrEF, 56% paroxysmal, 25% persistent, 19% permanent AF), as well as age, sex and ejection fraction matched patients with absent history of AF (n = 66; age 63.4 ± 10.6 years, 67% male, 47% HFrEF) were included. Patients with AF were further divided into those with paroxysmal AF (in sinus rhythm - AF SR : n = 38, age 71.4 ± 9.2, 73% male), and those with AF at the time of the study visit., Results: Retinal microvascular function was impaired in patients with AF compared to patients without AF (FIDart% 1.1% [0.3-2.8] vs. 2.7% [1.3-5.1], p < 0.001). Patients currently in AF have poorer retinal microvascular function (FIDart% 0.8% [0.1-1.9) compared to patients with a history of AF but currently in SR at the time of retinal function measurement (1.5% [0.6-4.9] p = 0.017). In patients with AF, impaired retinal vascular function was independently associated with larger left atrial volume (mean 49.8 ± 18.4), even after correction for confounding factors in different models (SCR = -0. 251 to -0.256, p = 0.035-0.01)., Conclusions: AF in patients with heart failure is associated with impaired vascular function, even if currently in sinus rhythm. The association of retinal microvascular dysfunction with left atrial volume, a surrogate for elevated cardiac filling pressures, may further highlight the important interplay between the vasculature and elevated filling pressures in the development of AF., Competing Interests: Declaration of Competing Interest VAR, DN and TH have no conflict of interest to declare. NL declares fees from Alnylam and Pfizer. IS declares in the last 10 years and until 2022 consulting fees, travel grant and honoraria from Amgen, Astra Zeneca, Daiichi Sankio, Medtronic, MSD, Novartis, Recordati, Sanofi und Servier unrelated to the topic of the paper. AJF declares fees from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Imedos Systems, Medtronic, MSD, Mundipharma, Novartis, Pierre Fabre, Pfizer, Roche, Schwabe Pharma, Vifor, and Zoll, as well as grant support by Novartis, AstraZeneca and Berlin Heart unrelated to this article. MPN declares speaker fees from AstraZeneca, Imedos Systems and Vifor Pharma, advisory board compensation from Boehringer Ingelheim and grant support by Amgen, unrelated to this article. FR has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years (remuneration for the time spent in activities, such as participation as steering committee member of clinical trials and member of the Pfizer Research Award selection committee in Switzerland, were made directly to the University of Zurich). The Department of Cardiology (University Hospital of Zurich/University of Zurich) reports research-, educational- and/or travel grants from Abbott, Amgen, Astra Zeneca, Bayer, Berlin Heart, B. Braun, Biosense Webster, Biosensors Europe AG, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Bracco, Cardinal Health Switzerland, Corteria, Daiichi, Diatools AG, Edwards Lifesciences, Guidant Europe NV (BS), Hamilton Health Sciences, Kaneka Corporation, Kantar, Labormedizinisches Zentrum, Medtronic, MSD, Mundipharma Medical Company, Novartis, Novo Nordisk, Orion, Pfizer, Quintiles Switzerland Sarl, Roche Diagnostics, Sahajanand IN, Sanofi, Sarstedt AG, Servier, SIS Medical, SSS International Clinical Research, Terumo Deutschland, Trama Solutions, V- Wave, Vascular Medical, Vifor, Wissens Plus, ZOLL. The research and educational grants do not impact on his personal remuneration., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Imtroduction: The high-risk population of patients with cardiovascular (CV) disease or risk factors (RF) suffering from COVID-19 is heterogeneous. Several predictors for impaired prognosis have been identified. However, with machine learning (ML) approaches, certain phenotypes may be confined to classify the affected population and to predict outcome. This study aimed to phenotype patients using unsupervised ML technique within the International Postgraduate Course Heart Failure Registry for patients hospitalized with COVID-19 and Cardiovascular disease and/or RF (PCHF-COVICAV)., Material and Methods: Patients from the eight centres with follow-up data available from the PCHF-COVICAV registry were included in this ML analysis (K-medoids algorithm)., Results: Out of 617 patients included into the prospective part of the registry, 458 [median age: 76 (IQR:65-84) years, 55% male] were analyzed and 46 baseline variables, including demographics, clinical status, comorbidities and biochemical characteristics were incorporated into the ML. Three clusters were extracted by this ML method. Cluster 1 (n = 181) represents mainly women with the least number of overall comorbidities and cardiovascular RF. Cluster 2 (n = 227) is characterized mainly by men with non-CV conditions and less severe symptoms of infection. Cluster 3 (n=50) mainly represents men with the highest prevalence of cardiac comorbidities and RF, more extensive inflammation and organ dysfunction with the highest 6-month all-cause mortality risk., Conclusions: The ML process has identified three important clinical clusters from hospitalized COVID-19 CV and/or RF patients. The cluster of males with severe CV disease, particularly HF, and multiple RF presenting with increased inflammation had a particularly poor outcome.

Acute myocarditis covers a wide spectrum of clinical presentations, from uncomplicated myocarditis to severe forms complicated by hemodynamic instability and ventricular arrhythmias; however, all these forms are characterized by acute myocardial inflammation. The term "chronic inflammatory cardiomyopathy" describes a persistent/chronic inflammatory condition with a clinical phenotype of dilated and/or hypokinetic cardiomyopathy associated with symptoms of heart failure and increased risk for arrhythmias. A continuum can be identified between these two conditions. The importance of early diagnosis has grown markedly in the contemporary era with various diagnostic tools available. While cardiac magnetic resonance (CMR) is valid for diagnosis and follow-up, endomyocardial biopsy (EMB) should be considered as a first-line diagnostic modality in all unexplained acute cardiomyopathies complicated by hemodynamic instability and ventricular arrhythmias, considering the local expertise. Genetic counseling should be recommended in those cases where a genotype-phenotype association is suspected, as this has significant implications for patients' and their family members' prognoses. Recognition of the pathophysiological pathway and clinical "red flags" and an early diagnosis may help us understand mechanisms of progression, tailor long-term preventive and therapeutic strategies for this complex disease, and ultimately improve clinical outcomes.

Introduction: Heart failure with preserved ejection fraction (HFpEF) has been shown to be a long-term consequence of uncontrolled arterial hypertension (aHT). Other than that, hypertensive response to exercise (HRE) precedes aHT. We aim to evaluate the available evidence for a continuum of HRE, aHT and HFpEF., Methods: A literature search on PubMed was conducted to assembly the most recent data on the topic. After collecting the data, a qualitative analysis was instrumented., Results: 10 studies including 16,165 subjects were analyzed with respect to the association between HRE and the future risk of developing aHT. With the exception of one study, all reported on a positive association between HRE and the future development of aHT despite methodological issues related to different definitions for HRE. Furthermore, HRE was associated with an increased risk of coronary artery disease. Moreover, we analysed 6 studies including overall 1366 subjects investigating the association between HRE and HFpEF. In these studies, increased left atrial volume index (LAVI), elevated E/e' (as surrogate parameters of increased LV end-diastolic filling pressure and of diastolic dysfunction) and higher LV mass index have been proposed as independent predictor of HRE in patients with no known HFpEF diagnosis., Discussion and Conclusion: The literature search revealed suggestive data on a connection of HRE, aHT and HFpEF. HRE seems to be an independent risk factor for aHT and aHT in turn is one of the main risk factors for HFpEF. However, further research is needed to improve our knowledge of a possible continuum of disease., (© 2023. The Author(s).)

Background: Three-dimensional electroanatomical mapping (EAM) can be helpful to diagnose arrhythmogenic right ventricular cardiomyopathy (ARVC). Yet, previous studies utilizing EAM have not systematically used contact-force sensing catheters (CFSC) to characterize the substrate in ARVC, which is the current gold standard to assure adequate tissue contact., Objective: To investigate reference values for endocardial right ventricular (RV) EAM as well as substrate characterization in patients with ARVC by using CFSC., Methods: Endocardial RV EAM during sinus rhythm was performed with CFSC in 12 patients with definite ARVC and 5 matched controls without structural heart disease. A subanalysis for the RV outflow tract (RVOT), septum, free-wall, subtricuspid region, and apex was performed. Endocardial bipolar and unipolar voltage amplitudes (BVA, UVA), signal characteristics and duration as well as the impact of catheter orientation on endocardial signals were also investigated., Results: ARVC patients showed lower BVA vs. controls (p = 0.018), particularly in the subtricuspid region (1.4, IQR:0.5-3.1 vs. 3.8, IQR:2.5-5 mV, p = 0.037) and RV apex (2.5, IQR:1.5-4 vs. 4.3,IQR:2.9-6.1 mV, p = 0.019). BVA in all RV regions yielded a high sensitivity and specificity for ARVC diagnosis (AUC 59-78%, p < 0.05 for all), with the highest performance for the subtricuspid region (AUC 78%, 95% CI:0.75-0.81, p < 0.001, negative predictive value 100%). A positive correlation between BVA and an orthogonal catheter orientation (46°-90°:r = 0.106, p < 0.001), and a negative correlation between BVA and EGM duration (r = -0.370, p < 0.001) was found., Conclusions: EAM using CFSC validates previous bipolar cut-off values for normal endocardial RV voltage amplitudes. RV voltages are generally lower in ARVC as compared to controls, with the subtricuspid area being commonly affected and having the highest discriminatory power to differentiate between ARVC and healthy controls. Therefore, EAM using CFSC constitutes a promising tool for diagnosis of ARVC., Competing Interests: Declaration of Competing Interest AMS received educational grants through his institution from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, BMS/Pfizer, and Medtronic; and speaker /advisory board /consulting fees from Biotronik, Daichii-Sankyo, Medtronic, Novartis and StrideBio. CBB received speaker /advisory board /consulting fees from Johnson&Johnson, Abbott, AstraZeneca, Novartis, and Pfizer., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Epicardial adipose tissue (EAT) is a metabolically highly active tissue modulating numerous pathophysiological processes. The aim of this study was to investigate the association between EAT thickness and endothelial function in patients with heart failure (HF) across the entire ejection fraction spectrum., Methods and Results: A total of 258 patients with HF with an ejection fraction across the entire spectrum [HF with reduced ejection fraction (HFrEF), n = 168, age 60.6 ± 11.2 years; HF with preserved ejection fraction (HFpEF), n = 50, mean age 65.1 ± 11.9 years; HF with mildly reduced ejection fraction (HFmrEF), n = 32, mean age 65 ± 12] were included. EAT was measured with transthoracic echocardiography. Vascular function was assessed with flicker-light-induced vasodilation of retinal arterioles (FIDart%) and flow-mediated dilatation (FMD%) in conduit arteries. Patients with HFrEF have less EAT compared with patients with HFpEF (4.2 ± 2 vs. 5.3 ± 2 mm, respectively, P < 0.001). Interestingly, EAT was significantly associated with impaired microvascular function (FIDart%; r = -0.213, P = 0.012) and FMD% (r = -0.186, P = 0.022), even after multivariate correction for confounding factors (age, body mass index, hypertension, and diabetes; standardized regression coefficient (SRC) = -0.184, P = 0.049 for FIDart% and SRC = -0.178, P = 0.043 for FMD%) in HFrEF but not in HFpEF., Conclusions: Although less EAT is present in HFrEF than in HFpEF, only in HFrEF EAT is associated with vascular dysfunction. The diverging role of EAT in HF and its switch to a functionally deleterious tissue promoting HF progression provide the rationale to specifically target EAT, in particular in patients with reduced ejection fraction., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Patients with acute coronary syndromes (ACS) remain at risk of cardiovascular disease (CVD) recurrences. Peripheral artery disease (PAD) may identify a very high risk (VHR) group who may derive greater benefit from intensified secondary prevention., Methods: Among ACS-patients enrolled in the prospective multi-center Special Program University Medicine (SPUM), we assessed the impact of PAD on major cardiovascular events (MACE: composite of myocardial infarction, stroke and all-cause death) and major bleeding. Multivariate analysis tested the relation of each significant variable with MACE, as well as biomarkers of inflammation and novel markers of atherogenesis., Results: Out of 4787 ACS patients, 6.0% (n = 285) had PAD. PAD-patients were older (p < 0.001), with established CVD and signs of increased persistent inflammation (hs-CRP; 23.6 ± 46.5 vs 10.4 ± 27.2 mg/l, p < 0.001 and sFlt-1; 1399.5 ± 1501.3 vs 1047.2 ± 1378.6 ng/l, p = 0.018). In-hospital-death (3.2% vs 1.4%, p = 0.022) and -MACE (5.6% vs 3.0%, p = 0.017) were higher in PAD-patients. MACE at 1 year (18.6% vs 7.9%,p < 0.001) remained increased even after adjustment for confounders (Adj. HR 1.53, 95% CI: 1.14-2.08, p = 0.005). Major bleeding did not differ between groups (Adj. HR 1.18; 95% CI 0.71-1.97, p = 0.512). Although PAD predicted MACE, PAD-patients were prescribed less frequently for secondary prevention at discharge., Conclusions: In this real-world ACS patient cohort, concomitant PAD is a marker of VHR and is associated with increased and persistent inflammation, higher risk for MACE without an increased risk of major bleeding. Therefore, a history of PAD may be useful to identify those ACS patients at VHR who require more aggressive secondary prevention., Competing Interests: Declaration of Competing Interest LR received research grants to the institution by Abbott, Biotronik, Heartflow, Sanofi, Regeneron and speaker/consultation fees by Abbott, Amgen, AstraZeneca, Canon, Novo Nordisk, Medtronic, Sanofi, Occlutech, Vifor. TFL received outside this project research and educational grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daichi-Sankyo, Novartis, Sanofi, Servier and Vifor and honoraria from Amgen, Daichi-Sankyo, Novartis, Sanofi all Switzerland, DalCor International, Inbeeo-NonoNordisk, India, Pfizer UK, Philipps, Europe. All other authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: COVID-19 affects the cardiovascular system and ECG abnormalities may be associated with worse prognosis. We evaluated the prognostic value of ECG abnormalities in individuals with COVID-19., Methods: Multicentre cohort study with adults hospitalised with COVID-19 from 40 hospitals across 23 countries. Patients were followed-up from admission until 30 days. ECG were obtained at each participating site and coded according to the Minnesota coding criteria. The primary outcome was defined as death from any cause. Secondary outcomes were admission to the intensive care unit (ICU) and major adverse cardiovascular events (MACE). Multiple logistic regression was used to evaluate the association of ECG abnormalities with the outcomes., Results: Among 5313 participants, 2451 had at least one ECG and were included in this analysis. The mean age (SD) was 58.0 (16.1) years, 60.7% were male and 61.1% from lower-income to middle-income countries. The prevalence of major ECG abnormalities was 21.3% (n=521), 447 (18.2%) patients died, 196 (8.0%) had MACE and 1115 (45.5%) were admitted to an ICU. After adjustment, the presence of any major ECG abnormality was associated with a higher risk of death (OR 1.39; 95% CI 1.09 to 1.78) and cardiovascular events (OR 1.81; 95% CI 1.30 to 2.51). Sinus tachycardia (>120 bpm) with an increased risk of death (OR 3.86; 95% CI 1.97 to 7.48), MACE (OR 2.68; 95% CI 1.10 to 5.85) and ICU admission OR 1.99; 95% CI 1.03 to 4.00). Atrial fibrillation, bundle branch block, ischaemic abnormalities and prolonged QT interval did not relate to the outcomes., Conclusion: Major ECG abnormalities and a heart rate >120 bpm were prognostic markers in adults hospitalised with COVID-19., Competing Interests: Competing interests: ALPR is a member of Heart editorial board. There are no other competing interests to be declared by any of the authors., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Epicardial adipose tissue (EAT) is an endocrine and paracrine organ constituted by a layer of adipose tissue directly located between the myocardium and visceral pericardium. Under physiological conditions, EAT exerts protective effects of brown-like fat characteristics, metabolizing excess fatty acids, and secreting anti-inflammatory and anti-fibrotic cytokines. In certain pathological conditions, EAT acquires a proatherogenic transcriptional profile resulting in increased synthesis of biologically active adipocytokines with proinflammatory properties, promoting oxidative stress, and finally causing endothelial damage. The role of EAT in heart failure (HF) has been mainly limited to HF with preserved ejection fraction (HFpEF) and related to the HFpEF obese phenotype. In HFpEF, EAT seems to acquire a proinflammatory profile and higher EAT values have been related to worse outcomes. Less data are available about the role of EAT in HF with reduced ejection fraction (HFrEF). Conversely, in HFrEF, EAT seems to play a nutritive role and lower values may correspond to the expression of a catabolic, adverse phenotype. As of now, there is evidence that the beneficial systemic cardiovascular effects of sodium-glucose cotransporter-2 receptors-inhibitors (SGLT2-i) might be partially mediated by inducing favorable modifications on EAT. As such, EAT may represent a promising target organ for the development of new drugs to improve cardiovascular prognosis. Thus, an approach based on detailed phenotyping of cardiac structural alterations and distinctive biomolecular pathways may change the current scenario, leading towards a precision medicine model with specific therapeutic targets considering different individual profiles. The aim of this review is to summarize the current knowledge about the biomolecular pathway of EAT in HF across the whole spectrum of ejection fraction, and to describe the potential of EAT as a therapeutic target in HF.

Amyloidosis is a systemic disease characterized by extracellular deposits of insoluble amyloid in various tissues and organs. Cardiac amyloidosis is a frequent feature of the disease, causing a progressive, restrictive type of cardiomyopathy, and is associated with adverse clinical outcomes and increased mortality. The typical clinical presentation in patients with cardiac amyloidosis is heart failure (HF) with preserved ejection fraction. Most patients present with typical symptoms and signs of HF, such as exertional dyspnea, pretibial edema, pleural effusions and angina pectoris due to microcirculatory dysfunction. However, patients may also frequently encounter various arrhythmias, such as atrioventricular nodal block, atrial fibrillation and ventricular tachyarrhythmias. The management of arrhythmias in cardiac amyloidosis patients with drugs and devices is often a clinical challenge. Moreover, predictors of life-threatening arrhythmic events are not well defined. This review intends to give a deepened insight into the arrhythmic features of cardiac amyloidosis by discussing the pathogenesis of these arrhythmias, addressing the challenges in risk stratification and strategies for management in these patients.

Hypertrophic cardiomyopathy (HCM) follows highly variable paradigms and disease-specific patterns of progression towards heart failure, arrhythmias and sudden cardiac death. Therefore, a generalized standard approach, shared with other cardiomyopathies, can be misleading in this setting. A multimodality imaging approach facilitates differential diagnosis of phenocopies and improves clinical and therapeutic management of the disease. However, only a profound knowledge of the progression patterns, including clinical features and imaging data, enables an appropriate use of all these resources in clinical practice. Combinations of various imaging tools and novel techniques of artificial intelligence have a potentially relevant role in diagnosis, clinical management and definition of prognosis. Nonetheless, several barriers persist such as unclear appropriate timing of imaging or universal standardization of measures and normal reference limits. This review provides an overview of the current knowledge on multimodality imaging and potentialities of novel tools, including artificial intelligence, in the management of patients with sarcomeric HCM, highlighting the importance of specific "red alerts" to understand the phenotype-genotype linkage.

Background: In the general population, hypertensive response to exercise (HRE) predicts new-onset resting hypertension or other cardiovascular diseases., Methods: PubMed was searched for English articles published between January 1st 2000 and April 30th 2020. Additional studies were identified via reference lists of included studies. 92 papers were selected for full text analysis, finally 30 studies were included., Results: The results from 5 follow-up studies suggested an association between HRE and the risk of developing hypertension, while 10 studies reported a link with adverse cardiovascular events in the general population. Another study showed an association between HRE and future hypertension in athletes after a follow-up of 7 years. HRE in athletes was associated with left ventricular hypertrophy in three studies. Two other studies showed a link between HRE and focal myocardial fibrosis in triathletes and myocardial injury, respectively. One study found lower Apoliprotein-1 serum levels in athletes with HRE leading to a higher risk for cardiovascular disease. Only in one study no association with cardiovascular dysfunction in athletes with HRE was found., Conclusions: Based on current evidence, HRE is not a normal finding in athletes. If detected, it should be interpreted as a risk factor for future cardiovascular complications. Future research should address the adequate follow-up and management of athletes with HRE., Competing Interests: The authors declare that there are no conflicts of interest with respect to related consultancies, shareholdings, funding grants, research, authorship, or publication of this article., (Copyright © 2022 Laura Würzburger et al.)

The pathophysiological mechanisms underlying the development of the athlete's heart are still poorly understood. To characterize the intracavitary blood flows in the right ventricle (RV) and right-ventricular outflow tract (RVOT) in 2 healthy probands, patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and 2 endurance athletes, we performed 4D-MRI flow measurements to assess differences in kinetic energy and shear stresses. Time evolution of velocity magnitude, mean kinetic energy (MKE), turbulent kinetic energy (TKE) and viscous shear stress (VSS) were measured both along the whole RV and in the RVOT. RVOT regions had higher kinetic energy values and higher shear stresses levels compared to the global averaging over RV among all subjects. Endurance athletes had relatively lower kinetic energy and shear stresses in the RVOT regions compared to both healthy probands and ARVC patients. The athlete's heart is characterized by lower kinetic energy and shear stresses in the RVOT, which might be explained by a higher diastolic compliance of the RV., (© 2022. The Author(s).)

Background: Cardiac rehabilitation (CR) is strongly associated with all-cause mortality reduction in patients with coronary artery disease (CAD). The impact of CR on pathological risk factors, such as impaired glucose tolerance (IGT) and functional recovery remains under debate. The aim of the present study is to determine whether CR had a positive effect beside physical exercise improvement on pathological risk factors in IGT and diabetic patients with CAD., Methods: One hundred and seventy-one consecutive patients participating in a 3-month CR from January 2014 to June 2015 were enrolled. The primary endpoint was defined as an improvement of peak workload and VO2-peak; glycated hemoglobin (HbA1c) reduction was considered as secondary endpoint., Results: Euglycemic patients presented a significant improvement in peak workload compared to diabetic patients (from 5.75 ± 1.45 to 6.65 ± 1.84 METs vs. 4.8 ± 0.8 to 4.9 ± 1.4 METs , p = 0.018). VO2-peak improved in euglycemic patients (VO2-peak from 19.3 ± 5.3 to 22.5 ± 5.9 mL/min/kg, p = 0.003), while diabetic patients presented only a statistically significant trend (VO2-peak from 16.9 ± 4.4 to 18.0 ± 3.8 mL/min/kg, p < 0.056). Diabetic patients have benefited more in terms of blood glucose control compared to IGT patients (HbA1c from 7.7 ± 1.0 to 7.4 ± 1.1 compared to 5.6 ± 0.4 to 5.9 ± 0.5, p = 0.02, respectively)., Conclusions: A multidisciplinary CR program improves physical functional capacity in CAD setting, particularly in euglycemic patients. IGT patients as well as diabetic patients may benefit from a CR program, but long-term outcome needs to be clarified in larger studies.

Background: Left atrial (LA) fibrosis in patients with atrial fibrillation (AF) is associated with an increased risk of AF recurrence after catheter ablation. Therefore, we searched for clinical risk factors that confer an increased risk of LA fibrosis, which can influence the treatment strategy., Methods: We included 94 patients undergoing 3-dimensional electroanatomical voltage mapping-guided catheter ablation of AF. LA low-voltage areas during sinus rhythm as a surrogate parameter of fibrosis were measured with the CARTO3 mapping system and adjusted for LA volumes obtained by computed tomography. Blood tests including N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and echocardiographic parameters of left ventricular function were also analyzed., Results: Patients were 62.5 ± 11.4 years old, and 29% were female. LA fibrosis was present in 65%, with 50% having a fibrotic area > 5% (≥ Utah-Stage 1). Mean left ventricular ejection fraction (LVEF) was 53.9 ± 10.5%. Patients with LA fibrosis had higher NT-proBNP levels (869 ± 1056 vs. 552 ± 859 ng/L, p = 0.001) and larger LA volumes (body surface area-corrected 63.3 ± 19.3 vs. 80 ± 27.1 mL/m2, p = 0.003). In univariable analyses, LA fibrosis was significantly associated with female gender, older age, increased LA volumes, hypertension, statin therapy, higher NT-proBNP values, and echocardiographic E/e'. In bivariable analyses, higher NT-proBNP, echocardiographic parameters of diastolic dysfunction, female gender, older age, and higher DR-FLASH scores remained as independent predictors of LA fibrosis., Conclusions: In this single-center longitudinal study, surrogate parameters of elevated left-sided cardiac filling pressures such as higher NT-proBNP levels and higher echocardiographic E/e' values as well as female gender independently predicted the prevalence of LA fibrosis in patients referred for catheter ablation of AF.

Objective: The 2010 Task Force Criteria (TFC) have not been tested to differentiate ARVC from the athlete's heart. Moreover, some criteria are not available (myocardial biopsy, genetic testing, morphology of ventricular tachycardia) or subject to interobserver variability (right ventricular regional wall motion abnormalities) in clinical practice. We hypothesized that atrial dimensions are useful and robust to differentiate between both entities and proposed a new diagnostic score based upon readily available parameters including echocardiographic atrial dimensions., Methods: In this observational study, 21 patients with definite ARVC were matched for age, gender and body mass index to 42 athletes. Based on ROC analysis, the following parameters were included in the score: indexed right/left atrial volumes ratio (RAVI/LAVI ratio), NT-proBNP, RVOT measurements (PLAX and PSAX BSA-corrected), tricuspid annular motion (TAM), precordial TWI and depolarization abnormalities according to TFC., Results: ARVC patients had a higher RAVI/LAVI ratio (1.76 ± 1.5 vs. 0.87 ± 0.2, p < 0.001), lower right ventricular function (fac: 29 ± 10.1 vs. 42.2 ± 5%, p < 0.001; TAM: 19.8 ± 5.4 vs. 23.8 ± 3.8 mm, p = 0.001) and higher serum NT-proBNP levels (345 ± 612 vs. 48 ± 57 ng/L, p < 0.001). Our score showed a good performance, which is comparable to the 2010 TFC using those parameters, which are available in routine clinical practice (AUC93%, p < 0.001 (95%CI 0.874-0.995) vs. AUC97%, p < 0.001 (95%CI 0.93-1.00). A score of 6/12 points yielded a specificity of 91% and an improved sensitivity of 67% for ARVC diagnosis as compared to a sensitivity of 41% for the abovementioned readily available 2010 TFC., Conclusions: ARVC patients present with significantly larger RA compared to athletes, resulting in a greater RAVI/LAVI ratio. Our novel diagnostic score includes readily available clinical parameters and has a high diagnostic accuracy to differentiate between ARVC and the athlete's heart.

Aims: The aim of this study was to analyse the role of inflammation and established clinical scores in predicting acute kidney injury (AKI) after acute coronary syndromes (ACS)., Methods and Results: In a prospective multicentre cohort including 2034 patients with ACS undergoing percutaneous coronary intervention, high-sensitivity C-reactive protein (hsCRP), neutrophil count, neutrophil-to-lymphocyte ratio (NL-ratio), and creatinine were measured at the index procedure. AKI (n = 39, defined according to RIFLE criteria) and major cardiovascular and cerebrovascular events were adjudicated after 1 year. Associations between inflammation, AKI, and cardiac death (CD) were assessed by C-statistics and Cox proportional hazard models with log-rank test to compare survival. Patients with ACS with elevated neutrophil count >7.8 × 109/L, NL-ratio >5, combined neutrophil-count/creatinine, or NL-ratio/creatinine at baseline showed a higher incidence of AKI (all P < 0.05) and CD (all P < 0.001). The risk of AKI, CD, and their combination was increased in patients with higher neutrophil count/creatinine (heart rate (HR) = 3.7, 95% cardiac index (CI) 1.9-7.1; HR = 2.7, 95% CI 1.6-4.6; HR = 3.2, 95% CI 2.1-4.9); NL-ratio/creatinine (HR = 2.1, 95% CI 1.6-4.1; HR = 2.2, 95% CI 1.3-3.8; HR = 2.3, 95% CI 1.5-3.5); and hsCRP (HR = 1.8, 95% CI 0.9-3.5; HR = 2.2, 95% CI 1.3-3.6; HR = 1.9, 95% CI 1.2-2.8) after adjustment for age, diabetes, hypertension, previous heart failure, kidney function, haemodynamic instability at admission, statin, and renin-angiotensin-aldosterone antagonists use. Subjects with higher GRACE score 1.0/NL-ratio had higher rate of AKI, CD, and both (HR = 1.4, 95% CI 0.5-4.2; HR = 2.7, 95% CI 1.3-5.9; HR = 2.1, 95% CI 1-4.3)., Conclusions: Inflammation markers may predict AKI after correction for renal function at the index procedure. hsCRP performed better than the NL-ratio. However, the integration of inflammation markers to traditional risk factors or scores does not add prognostic information., Trial Registration: ClinicalTrials.gov, NCT01000701., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: The clinical presentation of cardiac sarcoidosis (CS) may resemble that of arrhythmogenic right ventricular cardiomyopathy (ARVC)., Objective: The purpose of this study was to identify clinical variables to better discriminate between patients with genetically determined ARVC and those with CS fulfilling definite 2010 ARVC Task Force Criteria (TFC)., Methods: In this multicenter study, 10 patients with CS fulfilling definite 2010 ARVC TFC were age and gender matched with 10 genetically proven ARVC patients. A cardiac 18 F-fluorodeoxyglucose positron emission tomographic ( 18 F-FDG PET) scan was required for patients to be included in the study., Results: The 2010 ARVC TFC did not reliably differentiate between the 2 diseases. CS patients presented with longer PR intervals, advanced atrioventricular block (AVB), and longer QRS duration (P <.001 and P = .009, respectively), whereas T-wave inversions (TWIs) in the peripheral leads were more common in ARVC patients (P = .009). CS patients presented with more extensive left ventricular involvement and lower left ventricular ejection fraction (LVEF), whereas ARVC patients had a larger right ventricular outflow tract (RVOT) (P = .044). PET scan positivity was only present in CS patients (90% vs 0%)., Conclusion: The 2010 ARVC TFC do not reliably differentiate between CS patients fulfilling 2010 ARVC TFC and those with hereditary ARVC. Prolonged PR interval, advanced AVB, longer QRS duration, right ventricular apical involvement, reduced LVEF, and positive 18 F-FDG PET scan should raise the suspicion of CS, whereas larger RVOT dimensions, subtricuspid involvement and peripheral TWI favor a diagnosis of hereditary ARVC., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The term athlete's heart describes structural, functional and electrical adaptations of the cardiovascular system due to repetitive intense exercise. Physiological cardiac adaptations in athletes, however, may mimic features of cardiac diseases and therefore make it difficult to distinguish physiological adaptions from disease. Furthermore, regular exercise may also lead to pathological adaptions that can promote or worsen cardiac disease (eg, atrial dilation/atrial fibrillation, aortic dilation/aortic dissection and rhythm disorders). Sudden cardiac death (SCD) is a major concern in sports cardiology, and preparticipation screening (PPS) has demonstrated to be effective in identifying athletes at risk for SCD. In Europe, PPS is advocated to include personal and family history, physical examination and ECG, with further workup including echocardiography only if the initial screening investigations show abnormal findings. We review the current available evidence for echocardiography as a screening tool for conditions associated with SCD in recreational and professional athletes and advocate to include screening echocardiography to be performed at least twice in an athlete's career. We recommend that the first echocardiography is performed during adolescence to rule out structural heart conditions associated with SCD that cannot be detected by ECG, especially mitral valve prolapse, coronary artery anomalies, bicuspid aortic valve and dilatation of the aorta. A second echocardiography could be performed from the age of 30-35 years, when athletes age and become master athletes, to especially evaluate pathological cardiac remodelling to exercise (eg, atrial and/or right ventricular dilation), late onset cardiomyopathies and wall motion abnormalities due to myocarditis or coronary artery disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

A sedentary lifestyle is a major modifiable risk factor for many chronic diseases. Lifestyle modification in order to increase exercise capacity is key in the prevention and rehabilitation of chronic diseases. This could be achieved by active commute. The aim of this study was to assess the effects of daily active commuting on physical activity (PA) and exercise capacity. Seventy-three healthy hospital employees (age: 46 ± 9 years, 38% male), with a predominantly passive way of commuting, were randomly assigned to two parallel groups, a control group (CG, N = 22) or an intervention group (IG, N = 51), which was further split into public transportation/active commuting (IG-PT, N = 25) and cycling (IG-C, N = 26). Both intervention groups were asked to reach 150 min/wk of moderate- to vigorous-intensity exercise during their commute for 1 year. CG maintained a passive commuting mode. All participants underwent assessment of anthropometry, risk factor stratification, and exercise capacity by a medical doctor at the Institute of Sports Medicine, Prevention and Rehabilitation. Weekly physical activity, using the International Physical Activity Questionnaire and commuting behavior, using an online diary, were used to assess physical activity. At the end of the study, the change in exercise capacity did significantly differ between IG and CG (P = .003, ES = 0.82). Actively covered distances through commuting significantly differed between groups (walking P = .026; cycling P < .001). Therefore, active commuting improves exercise capacity and can be recommended to the working population to increase exercise capacity., (© 2020 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Objectives: Alpine skiing is one of the most popular recreational winter sports and attracts millions of tourists every year alone in the Alpine region. Several studies highlight the positive effects of alpine skiing as aerobic physical training and isometric muscle activity that is able to increase exercise capacity and reduce cardiovascular risk factors. However, a certain cardiovascular risk mainly related to an abrupt increase of myocardial oxygen consumption during skiing especially in otherwise sedentary subjects and effects of hypoxia in untrained patients have to be acknowledged., Design: In this article, we provide an up-to-date evaluation of risks and benefits of alpine skiing in relation of cardiovascular disease and elderly persons., Methods: Narrative Review., Results: In the first section, the current recommendations of physical activity and effects of alpine skiing - with particular attention to the elderly population - are described. In the second section, the present knowledge regarding cardiovascular risk and alpine skiing is summarized and possible pathophysiological mechanisms are highlighted. Finally, a summary regarding actual clinical recommendations is provided., Conclusions: Alpine skiing may safely be recommended also to the elderly if certain precautions are applied, as the benefits outbalance the potential risks in most subjects., (Copyright © 2019 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Sports in Patients with Heart Disease: What Should Be Recommended? Abstract. Sports is recommended in the European guidelines for the prevention and initial treatment of many cardiovascular diseases as well as the metabolic syndrome. However, the individually recommended intensity and duration of physical activity that unfolds the maximal protective effects in terms of prevention, largely differs. Indeed, a J-curve relationship with regard to exercise training has been postulated, with the assumption that too much sports is equally harmful or potentially even more harmful than too little sports. In this review, we try to answer the question of how much and which sports is optimal for cardiac patients.

One night of a sleep study is the standard for diagnosis and exclusion of obstructive sleep apnea. Single testing requires high sensitivity of the test method and a stable disease of interest to warrant a low rate of false-negative tests. Obstructive sleep apnea is diagnosed and graded by conventional thresholds of apneas and hypopneas per hour of sleep, and treatment is usually initiated in the presence of symptoms. The aim of this study was to assess night-to-night variability of obstructive sleep apnea to reassess the current practice. Seventy-seven patients previously diagnosed with obstructive sleep apnea, randomised to continuous positive airway pressure withdrawal within four trials, performed nightly pulse-oximetry over 2 weeks while off continuous positive airway pressure. The main outcome of interest was the coefficient of variation of the oxygen desaturation index marking night-to-night variability in obstructive sleep apnea. Obstructive sleep apnea was categorised according to conventional thresholds using oxygen desaturation index (no obstructive sleep apnea: <5 per h; mild: 5-15 per h; moderate: 15-30 per h; and severe: >30 per h). High night-to-night variability of obstructive sleep apnea was evidenced by a coefficient of variation of oxygen desaturation index of 31.1% (SD 16.5). Differences in oxygen desaturation index of >10 per h between nights were found in 84.4% and shifts in obstructive sleep apnea severity category in 77.9% of patients. The probability of missing moderate obstructive sleep apnea was up to 60%. Variability was higher in less severe obstructive sleep apnea. Obstructive sleep apnea shows a considerable night-to-night variability. Single-night diagnostic sleep studies are prone to miscategorise obstructive sleep apnea if arbitrary thresholds are used. Thus, treatment decisions should be based less on the conventional derivatives from sleep studies, especially in patients with less severe obstructive sleep apnea., Clinical Trial Registration: www.controlled-trials.com (ISRCTN 93153804, ISRCTN 73047833) and www.clinicaltrials.gov (NCT01332175 & NCT02050425)., (© 2017 European Sleep Research Society.)

Background and Objective: Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Intermittent hypoxia, endothelial dysfunction and adipose tissue-mediated inflammation have all been linked to cardiovascular disease in OSA. We therefore explored the effect of OSA on relevant associated blood markers: adrenomedullin (ADM), endocan, endothelin-1 (ET-1), resistin and vascular endothelial growth factor (VEGF)., Methods: Patients with OSA, established on and compliant with continuous positive airways pressure (CPAP) therapy for >1 year were included from three randomized controlled trials, conducted at two centres. Patients were randomized to either continued therapeutic CPAP or sham CPAP (CPAP withdrawal) for 2 weeks. Blood markers were measured at baseline and at 14 days and the treatment effect between sham CPAP and therapeutic CPAP was analysed., Results: A total of 109 patients were studied (therapeutic CPAP n = 54, sham CPAP n = 55). Sham CPAP was associated with a return of OSA (between-group difference in oxygen desaturation index (ODI) 36.0/h, 95% CI 29.9-42.2, P < 0.001). Sham CPAP was associated with a reduction in ADM levels at 14 days (-26.0 pg/mL, 95% CI -47.8 to -4.3, P = 0.02), compared to therapeutic CPAP. Return of OSA was not associated with changes in endocan, ET-1, resistin or VEGF., Conclusion: Whilst CPAP withdrawal was associated with return of OSA, it was associated with an unexpected significant reduction in the vasodilator ADM and not with expected increases in hypoxia-induced markers, markers of endothelial function or resistin. We propose that the vascular effects occurring in OSA may be brought about by other mechanisms, perhaps partly through a reduction in ADM., (© 2016 Asian Pacific Society of Respirology.)

Background: Untreated OSA is associated with impaired health-related quality of life (QoL) and excessive daytime sleepiness, which have been shown to improve with treatment. The aim was to compare the effects of CPAP and a mandibular advancement device (MAD) on health-related QoL in OSA., Methods: MEDLINE and the Cochrane Library were searched up to November 2015 for randomized controlled trials (RCTs) comparing the effect of CPAP, MADs, or an inactive control treatment on health-related QoL assessed by the 36-Item Short Form Health Survey (SF-36) in OSA. Extraction of study characteristics, quality, and bias assessment were independently performed by three authors. A network meta-analysis using multivariate random-effects meta-regression was performed to assess treatment effects on the mental component score (MCS) and the physical component score (PCS) of the SF-36., Results: Of 1,491 identified studies, 23 RCTs were included in the meta-analysis (2,342 patients). Compared with an inactive control, CPAP was associated with a 1.7 point (95% CI, 0.1-3.2; P = .036) improvement in the MCS and a 1.7 point (95% CI, 0.5-2.9; P = .005) improvement in the PCS. MADs were associated with a 2.4 point (95% CI, 0.0-4.9; P = .053) and a 1.5 point (95% CI, -0.2 to 3.2; P = .076) improvement in the MCS and PCS, respectively, compared with inactive control treatments. There were no statistically significant differences between treatment effects of CPAP and MAD on the SF-36 scores., Conclusions: CPAP is effective in improving health-related QoL in OSA, and MADs may be just as effective, but further RCTs comparing the two treatments are required., (Copyright © 2017 American College of Chest Physicians. All rights reserved.)

Background:: Baroreceptors act as regulators of blood pressure (BP); however, its sensitivity is impaired in hypertensive patients. Among the recommendations for BP reduction, exercise training has become an important adjuvant therapy in this population. However, there are many doubts about the effects of resistance exercise training in this population., Objective:: To evaluate the effect of resistance exercise training on BP and baroreceptor sensitivity in spontaneously hypertensive rats (SHR)., Method:: Rats SHR (n = 16) and Wistar (n = 16) at 8 weeks of age, at the beginning of the experiment, were randomly divided into 4 groups: sedentary control (CS, n = 8); trained control (CT, n = 8); sedentary SHR (HS, n = 8) and trained SHR (HT, n = 8). Resistance exercise training was performed in a stairmaster-type equipment (1.1 × 0.18 m, 2 cm between the steps, 80° incline) with weights attached to their tails, (5 days/week, 8 weeks). Baroreceptor reflex control of heart rate (HR) was tested by loading/unloading of baroreceptors with phenylephrine and sodium nitroprusside., Results:: Resistance exercise training increased the soleus muscle mass in SHR when compared to HS (HS 0.027 ± 0.002 g/mm and HT 0.056 ± 0.003 g/mm). Resistance exercise training did not alter BP. On the other hand, in relation to baroreflex sensitivity, bradycardic response was improved in the TH group when compared to HS (HS -1.3 ± 0.1 bpm/mmHg and HT -2.6 ± 0.2 bpm/mmHg) although tachycardia response was not altered by resistance exercise (CS -3.3 ± 0.2 bpm/mmHg, CT -3.3 ± 0.1 bpm/mmHg, HS -1.47 ± 0.06 bpm/mmHg and HT -1.6 ± 0.1 bpm/mmHg)., Conclusion:: Resistance exercise training was able to promote improvements on baroreflex sensitivity of SHR rats, through the improvement of bradycardic response, despite not having reduced BP., Fundamento:: Os barorreceptores atuam como reguladores da pressão arterial (PA); no entanto, sua sensibilidade encontra-se prejudicada em pacientes hipertensos. Dentre as recomendações para a redução da PA, o treinamento físico tem se tornado um importante adjunto na terapia dessa população. Porém, ainda há diversos questionamentos sobre os efeitos de treinamento físico resistido nessa população., Objetivo:: Avaliar o efeito do treinamento físico resistido na PA e na sensibilidade de barorreceptores em ratos espontaneamente hipertensos (SHR)., Método:: Ratos SHR (n = 16) e Wistar (n = 16) com 08 semanas de idade foram aleatoriamente divididos em 4 grupos: controle sedentário (CS, n = 8); controle treinado (CT, n = 8); SHR sedentário (HS, n = 8) e SHR treinado (HT, n = 8). O treinamento físico foi realizado em aparato com degraus (1,1 × 0,18 m, 2 cm entre os degraus, 80° inclinação) com peso fixado na cauda, (5 vezes por semana durante 8 semanas). O controle barorreflexo da frequência cardíaca (FC) foi testado com estímulos de fenilefrina e nitroprussiato de sódio., Resultados:: O treinamento resistido foi capaz de aumentar a massa muscular do sóleo em ratos SHR (HS 0,027 ± 0,002 g/mm e HT 0,056 ± 0,003 g/mm). Não houve alteração da PA com o treinamento. Por outro lado, houve melhora na resposta bradicárdica da sensibilidade barorreflexa no grupo HT (HS -1,3 ± 0,1 bpm/mmHg e HT -2,6 ± 0,2 bpm/mmHg), no entanto, a resposta taquicárdica não foi alterada pelo exercício resistido (CS -3,3 ± 0,2 bpm/mmHg, CT -3,3 ± 0,1 bpm/mmHg, HS -1,47 ± 0,06 e HT -1,6 ± 0,1)., Conclusão:: O exercício físico resistido foi capaz de otimizar a sensibilidade barorreflexa dos ratos SHR por meio da melhora à resposta bradicárdica, apesar de não alterar a PA.

Background: Based on meta-analyses, the BP-lowering effect of CPAP therapy in patients with OSA is reported to be approximately 2 to 3 mm Hg. This figure is derived from heterogeneous trials, which are often limited by poor CPAP adherence, and thus the treatment effect may possibly be underestimated. We analyzed morning BP data from three randomized controlled CPAP withdrawal trials, which included only patients with optimal CPAP compliance., Methods: Within the three trials, 149 patients with OSA who were receiving CPAP were randomized to continue therapeutic CPAP (n = 65) or to withdraw CPAP (n = 84) for 2 weeks. Morning BP was measured at home before and after sleep studies in the hospital., Results: CPAP withdrawal was associated with a return of OSA (apnea-hypopnea index [AHI] at a baseline of 2.8/h and at follow-up of 33.2/h). Office systolic BP (SBP) increased in the CPAP withdrawal group compared with the CPAP continuation group by +5.4 mm Hg (95% CI, 1.8-8.9 mm Hg; P = .003) and in the home SBP group by +9.0 mm Hg (95% CI, 5.7-12.3 mm Hg; P < .001). Office diastolic BP (DBP) increased by +5.0 mm Hg (95% CI, 2.7-7.3 mm Hg; P < .001), and home DBP increased by +7.8 mm Hg (95% CI, 5.6-10.4 mm Hg; P < .001). AHI, baseline home SBP, use of statin drugs, sex, and the number of antihypertensive drugs prescribed were all independently associated with SBP change in multivariate analysis, controlling for age, BMI, smoking status, diabetes, and sleepiness., Conclusions: CPAP withdrawal results in a clinically relevant increase in BP, which is considerably higher than in conventional CPAP trials; it is also underestimated when office BP is used. Greater OSA severity is associated with a higher BP rise in response to CPAP withdrawal., Trial Registry: ClinicalTrials.gov; No.: NCT01332175 and NCT01797653) URL: www.clinicaltrials.gov and ISRCTN registry (ISRCTN 93153804) URL: http://www.isrctn.com/., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

There are limited data on the evolution of obstructive sleep apnoea (OSA) during continuous positive airway pressure (CPAP) therapy and whether this treatment is required every night. 125 OSA patients with an original oxygen desaturation index (ODI) >10 events per hour, established on CPAP, were asked to withdraw CPAP for four nights and performed ambulatory nocturnal pulse oximetry on the fourth night of CPAP withdrawal. An ODI >10 events per hour during pulse oximetry was considered to indicate persistent OSA. Patients not experiencing recurrence of OSA underwent repeat ambulatory pulse oximetry after a further 2-week period off CPAP. In 71% of the patients, OSA recurred after four nights of CPAP withdrawal (group 1); thus, OSA did not recur in 29% (group 2). 55% of group 2 had an ODI >10 events per hour after 2 weeks off CPAP; thus, 45% remained without a recurrence. In multivariate analysis, higher original ODI, longer duration of CPAP therapy, current smoking status and larger neck circumference were independently associated with a higher ODI after four nights of CPAP withdrawal (all p<0.05). Following CPAP withdrawal, a third of CPAP-treated patients do not experience significant recurrence of oxygen desaturations after 4 days and ∼10% do not after 2 weeks. Thus, a significant proportion of patients may be able to stop CPAP for short periods.

Background: Altered cardiac repolarization and increased dispersion of repolarization have been identified as risk factors for sudden cardiac death (SCD). The prevalence of and the mechanisms contributing to altered cardiac repolarization are currently unknown in COPD., Methods: In 91 COPD patients, 32 controls matched for age, cardiovascular risk and medication, and 41 healthy subjects, measures of cardiac repolarization and dispersion of repolarization (QTc interval, QT dispersion) were derived from 12-lead electrocardiography (ECG). Prevalence rates of heart rate corrected QT (QTc) >450ms and QT dispersion >60ms were determined to assess the number of subjects at risk for SCD. Univariate and multivariate analyses were used to identify possible factors contributing to altered cardiac repolarization., Results: QTc was found to be prolonged in 31.9% and QT dispersion in 24.2% of the COPD patients compared to 12.5% in matched controls and 0% in healthy subjects. The QTc interval was longer in COPD patients compared to matched and healthy controls respectively (437.9 ± 29.5 vs. 420.1 ± 25.3 ms, p = 0.001 and vs. 413.4 ± 18.2 ms, p < 0.001). QT dispersion was significantly increased in COPD patients compared to healthy subjects (45.4 (34.8 , 59.5) vs. 39.7 (29.3 , 54.8) ms, p = 0.049). Only oxygen saturation was independently associated with QTc duration in multivariate analysis (β = -0.29, p = 0.015)., Conclusion: One third of a typical COPD population has altered cardiac repolarization and increased dispersion of repolarization, which may be related to hypoxia. Altered cardiac repolarization may expose these patients to an increased risk for malignant ventricular arrhythmias and SCD.