I.R.C.C.S. Istituto Auxologico Italiano

In humans, motor resonance effects can be tracked by measuring the enhancement of corticospinal excitability by action observation. Uncovering factors driving motor resonance is crucial for optimizing action observation paradigms in experimental and clinical settings. In the present study, we deepen motor resonance properties for grasping movements. Thirty-five healthy subjects underwent an action observation task presenting right-hand grasping movements differing from their action goal. Single-pulse transcranial magnetic stimulation was applied over the left primary motor cortex at 100, 200, or 300 ms from the onset of the visual stimulus depicting the action. Motor-evoked potentials were recorded from four muscles of the right hand and forearm. Results show a muscle-specific motor resonance effect at 200 ms after movement but selectively for observing a socially relevant grasp towards another human being. This effect correlates with observers’ emotional empathy scores, and it was followed by inhibition of motor resonance at 300 ms post-stimulus onset. No motor resonance facilitation emerged while observing intransitive hand movement or object grasping. This evidence highlights the social side of motor resonance and its dependency on temporal factors.

The transoral endoscopic thyroidectomy vestibular approach (TOETVA) has demonstrated excellent cosmetic and clinical outcomes with low complication rates. In addition to a relatively steep learning curve, TOETVA offers a real alternative to open and minimally invasive techniques. TOETVA is indicated for hemithyroidectomies in patients without prior neck surgery. Technically, it involves a 10-mm incision on the inside of the lower lip, followed by subplatysmal hydrodissection to create a space between the platysma and infrahyoid musculature. Three trocars are inserted prementally through the lower lip approaches. In our clinical experience with TOETVA, several critical steps and appropriate solutions were defined: 1. team positioning and technical improvement using a 4 K laparoscopic tower; 2. lateral and cranial positioning of lateral trocars to avoid mental nerve injury; 3. initial hydrodissection of subplatysmal space; 4. use of a dissector that gradually creates the surgical field in the anterior neck; 5. infrahyoid musculature retraction with externally fixed sutures; 6. intraoperative neuromonitoring routinely performed through the trocars or percutaneously through a 1-mm incision; 7. specimen removal using a recovery bag. Our results confirm the feasibility and safety of TOETVA combined with a steep learning curve. Further studies are needed to determine potential indications in standard care.

Air pollution and obstructive sleep apnea (OSA) are both linked with cardiovascular co-morbidities and share similar pathophysiological mechanisms. A causal association between the two has been postulated. However, the results of the studies on this topic are conflicting mainly because of the lack of adjustment for important confounders such as seasonality and temperature. We aimed to evaluate if such an association exists in a highly polluted area like Lombardy region (Italy) when accounting for all confounders. Data of adult patients seen at the Sleep Disorder Centre in Milan from 2010 to 2020 were analysed and the main polygraphic data were retrieved. Air pollutant concentrations of the following pollutants NO2, O3, PM2.5, and PM10 were collected through monitoring stations. A total of 3493 patients were included: males (2358, 67.5%) mean age 60.1 (SD = 14.3) years, BMI 29.2 (6.2) kg/m2, mean AHI 16.5 (18.1) events/h. After adjusting for all confounders, in the multivariable analysis, the only associations that remained significant were long-term exposure to O3 with indexes of OSA severity (AHI and ODI) but only in spring. Furthermore, a positive association was seen between long-term exposure to PM10 and ODI but in springtime only. The findings of the current study does not support an association between fine particulate matter and OSA severity.

Pulmonary hypertension (PH) is a common complication of diseases affecting the left heart, mostly found in patients suffering from heart failure, with or without preserved left ventricular ejection fraction. Initially driven by a passive increase in left atrial pressure (postcapillary PH), several mechanisms may lead in a subset of patient to significant structural changes of the pulmonary vessels or a precapillary component. In addition, the right ventricle may be independently affected, which results in right ventricular to pulmonary artery uncoupling and right ventricular failure, all being associated with a worse outcome. The differential diagnosis of PH associated with left heart disease versus pulmonary arterial hypertension (PAH) is especially challenging in patients with cardiovascular comorbidities and/or heart failure with preserved ejection fraction (HFpEF). A stepwise approach to diagnosis is proposed, starting with a proper clinical multidimensional phenotyping to identify patients in whom hemodynamic confirmation is deemed necessary. Provocative testing (exercise testing, fluid loading, or simple leg raising) is useful in the cath laboratory to identify patients with abnormal response who are more likely to suffer from HFpEF. In contrast with group 1 PH, management of PH associated with left heart disease must focus on the treatment of the underlying condition. Some PAH-approved targets have been unsuccessfully tried in clinical studies in a heterogeneous group of patients, some even leading to an increase in adverse events. There is currently no approved therapy for PH associated with left heart disease.

The relative contribution of small (sEVs) and large extracellular vesicles (lEVs) to the total plasma procoagulant potential is not yet well defined. Thus, we compared total and TFpos-sEVs and -lEVs isolated from healthy subjects and COVID-19 patients during the acute phase of the infection and after symptom remission in terms of (1) vesicle enumeration using nanoparticle tracking assay, imaging flow cytometry, and TF immunofluorescence localization in a single-vesicle analysis using microarrays; (2) cellular origin; and (3) TF-dependent Xa generation capacity, as well as assessing the contribution of the TF inhibitor, TFPI. In healthy subjects, the plasma concentration of CD9/CD63/CD81pos sEVs was 30 times greater than that of calceinpos lEVs, and both were mainly released by platelets. Compared to lEVs, the levels of TFpos-sEVs were 2-fold higher. The TF-dependent Xa generation capacity of lEVs was three times greater than that of sEVs, with the latter being hindered by TFPI. Compared to HSs, the amounts of total and TFpos-sEVs and -lEVs were significantly greater in acute COVID-19 patients, which reverted to the physiological values at the 6-month follow-up. Interestingly, the FXa generation of lEVs only significantly increased during acute infection, with that of sEV being similar to that of HSs. Thus, in both healthy subjects and COVID-19 patients, the TF-dependent procoagulant potential is mostly sustained by large vesicles.

Background COVID-19 has been associated with a higher risk of post-acute complications. Our aim was to analyze and compare post-acute cardiovascular complications of COVID-19 survivors of the first and second/third pandemic waves in Lombardy, in both hospitalized and non-hospitalized COVID-19 patients. Methods and results We included adults aged ≥40 years infected during the first and second/third waves of COVID-19 pandemic. The follow-up initiated 30 days after COVID-19 diagnosis and continued up to 9 months. Hazard ratios (HRs) and 95% confidence intervals (CIs) of the post-acute cardiovascular outcomes were calculated against an inverse probability treatment weighted control group. Subgroup analysis were performed by age classes, sex, previous cardiovascular disease and stratified by COVID-19 hospitalization status to explore the impact of COVID-19 severity on outcomes. Compared to the control group, COVID-19 patients had an increased risk of hospitalization for any cardiovascular complications (HR 1st wave 1.53 95% CI: 1.38–1.69; HR 2nd/3rd wave 1.25 95% CI: 1.19–1.31) and for individual cardiovascular outcomes, although HRs were higher in COVID-19 group from the 1st pandemic wave. The results were confirmed in the subgroup analyses. Of note, the risk for any cardiovascular disease was also evident even among individuals who were not hospitalized during the acute phase of the infection. Conclusion Our results provide evidence that COVID-19 is a risk factor for post-acute cardiovascular complications among different pandemic waves regardless of COVID-19 severity, age, sex and a history of cardiovascular diseases. Care strategies of people with COVID-19 should include cardiac monitoring.

We describe a case of amyotrophic lateral sclerosis (ALS) associated with Alzheimer’s disease (AD) and review the literature about the coexistence of the two entities, highlighting the following: mean age at onset is 63.8 years, with slight female predominance; ALS tends to manifest after cognitive impairment and often begins in the bulbar region; average disease duration is 3 years; cognitive phenotype is mostly amnestic; the pattern of brain involvement is, in most cases, consistent with AD. Our case and the reviewed ones suggest that patients with ALS and dementia lacking unequivocal features of FTD should undergo additional examinations in order to recognize AD.

Objective The study explored the change in handwritten signature in neurodegenerative diseases by using of a rater-based approach. Methods Four independent observers were required to compare a pair of signatures (on average, 5 years elapsed between the two signatures) made by 103 patients (mean age 72 years) with Alzheimer’s disease (AD) or frontotemporal dementia (FTD) and by 31 healthy participants (HC; mean age 73 years), judging their change according to a 0–1 rating scale (0 = similar or 1 = different). If a signature change was detected, the rater had also to report which signature features (spatial layout, omitted/added/switched letters or names, shape of letter, pen-flow) changed on the same 0–1 scale. For the AD and FTD groups, one signature was collected prior to the diagnosis of dementia, the other subsequent. Results A signature change was reported by raters in 36% of AD patients, 44% of FTD, and 17% of HC, with significant differences between both clinical groups and HC (vs. AD, p = .01; vs. FTD, p = .001). There was not a distinctive marker of the signature change (i.e., feature change) in patients with dementia. Moreover, the signature changes in neurological patients were unrelated to their clinical and demographic characteristics (age, sex, education, time elapsed between the two signatures, Mini-mental State Examination score). Conclusion The findings suggest a resistance of handwritten signature in neurodegenerative diseases and in physiological aging, also suggesting that the signature may be an unreliable indicator of the cognitive status in AD and FTD, at least if subjectively evaluated.

Objective The aims of our study were to investigate the effect of the extent and location of late gadolinium enhancement (LGE) on the left atrium (LA) function in patients with acute myocarditis (AM) using cardiovascular magnetic resonance (CMR). Method This retrospective study performed CMR scans in 113 consecutive patients (89 males, 24 females; mean age 45.8 ± 17.3 years) with AM that met the updated Lake Louise criteria. Reservoir, conduit, and booster LA functions were analyzed by CMR feature tracking using dedicated software. Besides LA strain measurements, myocardial scar location and extent were assigned and quantified by LGE imaging. Results AM patients with septal LGE had impaired reservoir, conduit, and conduit strain rate function in comparison with AM patients with non-septal LGE ( p = 0.001, for all). In fully adjusted multivariable linear regression, reservoir and conduit were significantly associated with left ventricle (LV) LGE location ( β coefficient = 8.205, p = 0.007; β coefficient = 5.185, p = 0.026; respectively). In addition, LA parameters decreased according to the increase in the extent of LV fibrosis (LGE ≤ 10%; LGE 11–19%; LGE ≥ 20%). After adjustment in multivariable linear regression, the association with LV LGE extent was no longer statistically significant. Conclusion In patients with acute myocarditis, LA function abnormalities are significantly associated with LV LGE location, but not with LGE extent. Septal LGE is paralleled by a deterioration of LA reservoir and conduit function. Clinical relevance statement Left atrium dysfunction is associated with the presence of late gadolinium enhancement in the left ventricle septum and can be useful in the clinical prognostication of patients with acute myocarditis, allowing individually tailored treatment. Key Points • Myocardial fibrosis is related to atrial impairment. • The location of myocardial fibrosis is the main determinant of atrial dysfunction in myocarditis patients. • The quantification of atrial mechanisms may provide more in-depth insight into myocarditis pathophysiology.

Background: Aortic valve neocuspidalization aims to replace the three aortic cusps with autologous pericardium pre-treated with glutaraldehyde and is a surgical alternative to the classical aortic valve replacement.Image-based patient-specific computational fluid dynamics allows the derivation of shear stress on the aortic wall (WSS). Previous studies support a potential link between increased WSS and histological alterations of the aortic wall.The aim of this study is to compare the WSS of the ascending aorta in patients undergoing aortic valve neocuspidalization vs aortic valve replacement with biological prostheses. Methods: This is a prospective nonrandomized clinical trial. Each patient underwent 4D-flow cardiac magnetic resonance scan after surgery, which informed patient-specific computational fluid dynamics models to evaluate WSS at the ascending aortic wall. The adjusted variables were calculated by summing the residuals obtained from a multivariate linear model (with ejection fraction and left ventricle outflow tract-aorta angle as covariates) to the mean of the variables. Results: 10 patients treated with aortic valve neocuspidalization were enrolled and compared with 10 aortic valve replacement patients. Aortic valve neocuspidalization group showed a significantly lower WSS in the outer curvature segments of the proximal and distal ascending aorta as compared to aortic valve replacement patients (p 0.0179 and 0.0412, respectively). WSS levels remained significantly lower along the outer curvature of the proximal aorta in the aortic valve neocuspidalization population, even after adjusting the WSS for the ejection fraction and the left ventricle outflow tract-aorta angle (2.44 Pa(2.17-3.01) vs 1.94 Pa(1.72-2.01), p 0.02). Conclusions: Aortic valve neocuspidalization hemodynamical features are potentially associated with a lower WSS in the ascending aorta as compared to commercially available bioprosthetic valves.

Motor interactions require observing and monitoring a partner's performance as the interaction unfolds. Studies in monkeys suggest that this form of social monitoring might be mediated by the activity of the ventral premotor cortex (vPMc), a critical brain region in action observation and motor planning. Our previous fMRI studies in humans showed that the left vPMc is indeed recruited during social monitoring, but its causal role is unexplored. In three experiments, we applied online anodal or cathodal transcranial direct current stimulation over the left lateral frontal cortex during a music-like interactive task to test the hypothesis that neuromodulation of the left vPMc affects participants' performance when a partner violates the agent's expectations. Participants played short musical sequences together with a virtual partner by playing one note each in turn-taking. In 50% of the trials, the partner violated the participant's expectations by generating the correct note through an unexpected movement. During sham stimulation, the partner's unexpected behavior led to a slowdown in the participant's performance (observation-induced posterror slowing). A significant interaction with the stimulation type showed that cathodal and anodal transcranial direct current stimulation induced modulation of the observation-induced posterror slowing in opposite directions by reducing or enhancing it, respectively. Cathodal stimulation significantly reduced the effect compared to sham stimulation. No effect of neuromodulation was found when the partner behaved as expected or when the observed violation occurred within a context that was perceptually matched but noninteractive in nature. These results provide evidence for the critical causal role that the left vPMc might play in social monitoring during motor interactions, possibly through the interplay with other brain regions in the posterior medial frontal cortex.

The aim of this systematic review and meta-analysis was to evaluate the effectiveness of the osteopathic manipulative treatment (OMT) in adults with irritable bowel syndrome (IBS). A literature resview was carried out on the following databases: PubMed, Embase, Cochrane, Cinahl, Scopus, PEDro and ClinicalTrials.gov. 350 articles were recovered. Eligibility criteria were evaluated by two independent reviewers, including randomized controlled trials (RCTs), quasi-RCTs, or ongoing RCTs with OMT compared to any kind of control in patients diagnosed with IBS. Six studies (five RCTs and one ongoing RCT) were considered eligible. Four RCTs were classified as some concerns and one as high risk of bias. In the meta-analysis, OMT compared to sham/no intervention showed statistically significant results for abdominal pain (effect size ES = −1.14 [−1.66, −0.62]; p < 0.0001) and constipation (ES = −0.66 [−1.12, −0.20]; p = 0.005). Instead, OMT was not superior to the control for the IBS symptoms measured with the IBS Severity Score and the Likert scale (ES = −0.34 [−0.83, 0.16]; p = 0.19), and diarrhea (ES = −1.20 [−2.84, 0.43]; p = 0.15). The quality of evidence was “low” for IBS symptoms in general for abdominal pain and constipation, while it was judged as “very low” for diarrhea. OMT turns out to be safe in the treatment of IBS without major adverse effects. OMT may be effective in IBS patients, however the results must be interpreted carefully due to the low methodological quality of the studies.

Introduction: The pathophysiology of obstructive sleep apnea (OSA) is multi-factorial and complex. Varying OSA's pathophysiological traits have been identified, including pharyngeal collapsibility, upper airway muscle reactivity, arousal threshold, and regulation of the ventilatory drive. Being CPAP of difficult tolerance and other interventions reserved to specific subpopulations new pharmacological treatments for OSA might be resolutive. Areas covered: Several existing and newly developed pharmacological drugs can impact one or more endotypes and could therefore be proposed as treatment options for sleep disordered breathing. With this review we will explore different pathophysiological traits as new targets for OSA therapy. This review will summarize the most promising pharmacological treatment for OSA accordingly with their mechanisms of action on upper airway collapsibility, muscle responsiveness, arousal threshold, and loop gain. Expert opinion: Only understanding the pathophysiological traits causing OSA in each patient and placing the disease in the framework of patient comorbidities, we will be able to evolve interventions toward OSA. The development of new drug's combinations will permit different approaches and different choices beside conventional treatments. In the next future, we hope that sleep specialists will select the treatment for a specific patient on the base of its pathophysiology, defining a precision medicine for OSA.

Objective: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. Methods: This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard. Results: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-β2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%. Conclusion: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Objective To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. Methods This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators’ consensus as the gold standard. Results The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1–7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti–β 2 -glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. Conclusion These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Over the last 25 years, the Europace journal has greatly contributed to dissemination of research and knowledge in the field of syncope. More than 400 manuscripts have been published in the journal. They undoubtedly improved our understanding of syncope. This symptom is now clearly differentiated from other forms of transient loss of consciousness. The critical role of vasodepression and/or cardioinhibition as final mechanisms of reflex syncope is emphasized. Current diagnostic approach sharply separates between cardiac and autonomic pathways. Physiologic insights have been translated, through rigorously designed clinical trials, into non-pharmacological or pharmacological interventions and interventional therapies. The following manuscript is intended to give the reader the current state of the art of knowledge of syncope by highlighting landmark contributions of the Europace journal.

Background and aims: Benefit of tricuspid regurgitation (TR) correction and timing of intervention are unclear. This study aimed to compare survival rates after surgical or transcatheter intervention to conservative management according to TR clinical stage as assessed using the TRI-SCORE. Methods: 2,413 patients with severe isolated functional TR were enrolled in TRIGISTRY (1217 conservatively managed, 551 isolated tricuspid valve surgery and 645 transcatheter valve repair). The primary endpoint was survival at 2 years. Results: The TRI-SCORE was low (≤3) in 32%, intermediate (4-5) in 33% and high (≥6) in 35%. A successful correction was achieved in 97% and 65% of patients in the surgical and transcatheter groups, respectively. Survival rates decreased with the TRI-SCORE in the three treatment groups (all P < 0.0001). In the low TRI-SCORE category, survival rates were higher in the surgical and transcatheter groups than in the conservative management group (93%, 87% and 79%, respectively; P = 0.0002). In the intermediate category, no significant difference between groups was observed overall (80%, 71% and 71%, respectively; P = 0.13) but benefit of the intervention became significant when the analysis was restricted to patients with successful correction (80%, 81% and 71%, respectively; P = 0.009). In the high TRI-SCORE category, survival was similar between groups even when restricted to patients with successful correction (61%, 68% and 58% respectively, P = 0.08). Conclusion: Survival progressively decreased with the TRI-SCORE irrespective of treatment modality. Compared to conservative management, an early and successful surgical or transcatheter intervention improved 2-year survival in patients at low and, to a lower extent, intermediate TRI-SCORE, while no benefit was observed in the high TRI-SCORE category.

In the early nineties, few years before the birth of Europace, the clinical and scientific world of familial arrhythmogenic conditions was revolutionized by the identification of the first disease-causing genes. The explosion of genetic studies over a 15-year period led to the discovery of major disease-causing genes in practically all channelopathies and cardiomyopathies, bringing insight into the pathophysiological mechanisms of these conditions. The birth of next generation sequencing allowed a further step forward and other significant genes, as CALM1-3 in channelopathies and FLN C and TTN in cardiomyopathies were identified. Genotype-phenotype studies allowed the implementation of the genetic results in diagnosis, risk stratification, and therapeutic management with a different level of evidence in different arrhythmogenic conditions. The influence of common genetic variants, i.e. SNPs, on disease manifestation was proved in mid-twenties, and in the last 10 years with the advent of genome-wide association studies performed in familial arrhythmogenic diseases, the concept of polygenic risk score has been consolidated. Now, we are at the start of another amazing phase, i.e. the initiation of first gene therapy clinical trials.

Imaging plays an integral role in all aspects of managing heart disease and cardiac imaging is a core competency of cardiologists. The adequate delivery of cardiac imaging services requires expertise in both imaging methodology - with specific adaptations to imaging of the heart - as well as intricate knowledge of heart disease. The European Society of Cardiology (ESC) and the European Association of Cardiovascular Imaging (EACVI) of the ESC have developed and implemented a successful education and certification programme for all cardiac imaging modalities. This programme equips cardiologists to provide high quality competency-based cardiac imaging services ensuring they are adequately trained and competent in the entire process of cardiac imaging, from the clinical indication via selecting the best imaging test to answer the clinical question, to image acquisition, analysis, interpretation, storage, repository, and results dissemination. This statement emphasizes the need for competency-based cardiac imaging delivery which is key to optimal, effective and efficient, patient care.

Imaging plays an integral role in all aspects of managing heart disease and cardiac imaging is a core competency of cardiologists. The adequate delivery of cardiac imaging services requires expertise in both imaging methodology - with specific adaptations to imaging of the heart - as well as intricate knowledge of heart disease. The European Society of Cardiology (ESC) and the European Association of Cardiovascular Imaging (EACVI) of the ESC have developed and implemented a successful education and certification programme for all cardiac imaging modalities. This programme equips cardiologists to provide high quality competency-based cardiac imaging services ensuring they are adequately trained and competent in the entire process of cardiac imaging, from the clinical indication via selecting the best imaging test to answer the clinical question, to image acquisition, analysis, interpretation, storage, repository, and results dissemination. This statement emphasizes the need for competency-based cardiac imaging delivery which is key to optimal, effective and efficient, patient care.