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Funding Acknowledgements Type of funding sources: None. Background PCSK9 inhibitors (PCSK9i) are a novel drug class indicated for the treatment of dyslipidaemia. PCSK9i have been shown to remarkably reduce cardiovascular events in patients at high risk, but little data is currently available regarding the incidence of atrial fibrillation, no reports exist on ventricular events or other cardiac arrhythmias, and is not documented if this drug class is safe regarding arrhythmias as a potential side effect. Purpose To study the incidence of arrhythmias in patients before and after treatment with PCSK9i. Methods All consecutive patients starting treatment with PCSK9 inhibitors, either evolocumab or alirocumab, were consecutively enrolled in two high-volume Italian arrhythmia centres. All patients were treated according to ESC guidelines for primary and secondary prevention. All patients failed to achieve the recommended LDL goals with standard treatment before the introduction of PCSK9i. Patients with familial hypercholesterolemia were excluded. All arrhythmic endpoints were collected in a one-year time frame before and after the first dose of PCSK9i. Results 191 patients were enrolled (mean age 63±15 years, 76.6% males) and followed up for one year. 13.2% were labelled as "statin-intolerant" and were treated only with ezetimibe, all the others had PCSK9i prescription on top of both statin and ezetimibe. The recommended LDL threshold was reached in 45.1% of patients at very high-risk and 76.7% at high-risk. 14.9% of all patients had a history of PACs and 15.6% had a history of PVCs. 7.8% had a previous diagnosis of atrial fibrillation, 2.1% of TRNAV and 6.4% of sustained ventricular arrhythmias. These 6.4% all had an ICD implanted for secondary prevention, while another 0.9% had a primary prevention indication. The total number of PACs in 24 hours decreased from 1260 to 800, although the difference was not statistically significant (p=0.058). Similar results were noted for PVCs (from 271 to 195 in 24 hours; p=0.089). The one-year incidence was 6.1% for atrial fibrillation, 2.3% for TRNAV and 3.8% for sustained ventricular arrhythmias, with no difference between the year before (all p=NS). Of all patients with an ICD and a history of appropriate ICD therapies (n=11, 5.7%) only one experienced appropriate therapies in the year after PCSK9i started. Conclusions The treatment with PCSK9 inhibitors does not significantly modify the risk of supraventricular or ventricular arrhythmias in patients with non-familial hypercholesterolemia. Preliminary data support the safety of this class of drug also regarding arrhythmic events.

Funding Acknowledgements Type of funding sources: None. Background Cardiac amyloidoses (CA) are an increasingly recognized group of infiltrative cardiomyopathies associated with high risk of heart failure, thromboembolic events, arrhythmias, and sudden death. Endomyocardial biopsy may be required to differentiate the amyloid type (mainly, Immunoglobulin light chain [AL] versus transthyretin-related [ATTR]) in some cases. Purpose to provide a first description of electroanatomical characteristics of amyloid cardiomyopathy, and relate them to endomyocardial biopsy findings. Methods we enrolled ten consecutive patients (median age, 68 [63-77]; male, 50%) in an observational, retrospective study. All of them had a clinical diagnosis of CA, but a diagnosis of CA type was hampered by the presence of inconclusive or discordant laboratory-imaging findings (abnormal serum free light chain assay and positive bone scintigraphy, n=5; ambiguous imaging results, n=4; abnormal serum free light chain assay and TTR gene mutation, n=1). Therefore, all patients underwent right ventricular high-density electroanatomical mapping (EAM) using a multipolar catheter (Advisor HD Grid, Abbott), and EAM-guided endomyocardial biopsy (EMB). We recorded electrogram features at EMB sampling site, and explored their correlation with histological findings with mixed effect models. Results The clinical, electroanatomical, and histological features of enrolled patients according to the EMB-proven type of CA (AL, n=6; ATTR, n=4) are resumed in Table. Electrogram amplitudes in both the bipolar and the unipolar configuration were generally normal both in the overall right ventricle, and at EMB sites. We found a significant correlation between both unipolar and bipolar electrogram amplitude and the percentage of both amyloid tissue (p15% amyloid tissue infiltration according to Youden index was 9.1 mV (sensitivity, 43%; specificity, 100%; accuracy, 77%). Conclusion CA is associated with normal electrogram amplitudes using ahigh density mapping catheter and conventional voltage cutoffs. Nevertheless, unipolar electrogram amplitude is strongly related to the extent of amyloid infiltration, and unipolar voltage15% amyloid tissue deposition.

Funding Acknowledgements Type of funding sources: None. Background Catheter ablation is an increasingly used treatment option for patients with recurrent ventricular tachycardia (VT) or electrical storm (ES). The QDOT Micro (QDOT) Catheter (Biosense Webster) is a novel radiofrequency ablation catheter that was found to allow rapid and effective pulmonary vein isolation among patients with atrial fibrillation. There is no published data on the safety and efficacy of catheter ablation for VT using the QDOT catheter, and few data allow a direct comparison of different technologies in this setting. Purpose to assess outcomes of CA for VT among patients with structural heart disease using the QDOT catheter, and compare them to those observed with the Thermocool Smarttouch (TC-ST, Biosense Webster) catheter. Methods we conducted a dual-center, observational, prospective study enrolling patients with structural heart disease and recurrent VT/ES undergoing catheter ablation with the QDOT catheter. For comparison, we performed a 1:1 propensity score matching to identify patients who underwent VT CA with the TC-ST catheter, using the nearest neighbor method. Propensity score was based on gender, age, etiology of structural heart disease, left ventricular ejection fraction, electrical storm, and number of previous CAs for VT. The primary efficacy outcome was freedom from recurrent VT, as assessed by implantable defibrillator (ICD) interrogation; the primary safety outcome was in-hospital complications. Results Forty propensity-matched patients were included in the analysis (QDOT, n=20; TC-ST, n=20); baseline clinical characteristics are resumed in Table. After a median follow-up of 7 months, survival free from any recurrent VT measured 74 (95% CI, 57-97)% and 69 (95% CI, 51-93)% in the QDOT and TC-ST groups, respectively (log-rank p=0.54, Figure A), while survival free from ICD shocks was 95 (95% CI, 86-100)% versus 84 (95% CI, 69-100)% (log-rank p=0.26, Figure B). There were no major complications in the QDOT group, while three patients (15%) in the TC-ST had a primary safety event (p=0.23; femoral pseudoaneurysm, n=1; cardiac tamponade, n=1; aortic cusp perforation, n=1). Conclusion In a cohort of patients with structural heart disease and recurrent VT or ES, the novel QDOT ablation catheter had similar efficacy and safety compared to the TC-ST catheter. Interestingly, no major procedural complications were observed with the QDOT catheter, suggesting that this device may be safe even in most challenging patients.

Funding Acknowledgements Type of funding sources: None. Background Left ventricular non-compaction (LVNC) is a rare, although underdiagnosed, cardiomyopathy deriving from the incomplete development of myocardial tissue. Its presentations range from heart failure to embolism and arrhythmic events with the latter being the most frequent cause of death. Purpose To define the incidence of arrhythmic complications in LVNC and describe the interplay between systolic dysfunction and ventricular events. Methods This is a retrospective evaluation of a prospectively-collected database including all consecutive patients with a definitive diagnosis of LVNC followed-up at the Cardiomyopathy Clinic of our institution from October 2009 to August 2022. We conducted a follow-up analyzing the possible correlation between baseline characteristics and a composite outcome of ventricular arrhythmias (sustained VT or VF), appropriate ICD interventions and sudden cardiac death (SCD). We also extracted a sample from our population with preserved LVEF and compared global longitudinal strain (GLS) in compacted and non-compacted segments. Results 44 patients (29 males, 65.9%) were enrolled in the study; 36 patients (81.8%) underwent a cardiac MRI and 34 (77.3%) resulted positive for Petersen criteria. 26 patients (59.1%) had positive echocardiographic criteria, while 18 patients (40.9%) were positive for both MRI and echocardiographic criteria. Five patients (11%) experienced an arrhythmic event during a median follow-up of 2 years (1 VT, 1 VF and 3 patients with appropriate ICD interventions). No clinical, ECG or lab predictors were found for arrhythmic events apart from a history of non-sustained or sustained ventricular arrhythmias, which was associated with a 36% increased risk of subsequent VT/VF episodes (RR 1.36; 95% CI 1.01-1.85; p=0.01). Notably, LVEF (which was ≤35% in 11% of the patients) was not able to significantly discriminate arrhythmic risk (50.7±13.0% vs. 50.2±7.8%; p=ns). Out of 9 patients with normal LVEF and normal GLS, the segmental LS resulted better in non-compacted cardiac segments vs. compacted ones (-20.0±4.6% vs. -17.5±4.9%; p=0.03). This was mainly due to an increase deformation of endocardial layers of non-compacted segments (-26.4±6.6% vs. -19.7±6.6%; p≤0.001), while epicardial layers were similar in compacted versus non-compacted segments. Conclusions LVNC represents a poorly understood condition where a mixture of genetic and molecular mechanisms create a fertile substrate for the origin of ventricular arrhythmias. Our population reflects this pattern by showing a high percentage (5.5%/year) of patients experiencing the composite outcome. GLS was higher in non-compacted segments due to an apparent hyperdeformation of endocardial layers. In our opinion, this evidence represents a valid resource and a useful weapon to distinguish LVNC from other differential diagnoses such as, for example, dilated cardiomyopathy.

Paolo Vincenzi,1 Massimo Stronati,2 Paolo Garelli,3 Diletta Gaudenzi,4 Gianfranco Boccoli,3 Roberto Starnari2 1Department of General Surgery, Ospedali Riuniti Marche Nord, Pesaro, Italy; 2Department of Anesthesiology, IRCSS-INRCA, Ancona, Italy; 3Department of General Surgery, IRCSS-INRCA, Ancona, Italy; 4Department of Perioperative Services, AOU “Ospedali Riuniti di Ancona”, Ancona, ItalyCorrespondence: Paolo Vincenzi, Department of General Surgery, Ospedali Riuniti Marche Nord, Piazzale Cinelli n 1, Pesaro, 61121, Italy, Tel +39 3394578495, Email paolo.vincenzi1981@gmail.comPurpose: Several studies have applied lumbar spinal anesthesia (SA) with isobaric/hyperbaric bupivacaine and opioids in elective laparoscopic cholecystectomy (LC), documenting a superiority of the methodic over general anesthesia (GA) in terms of perioperative pain, nausea, and vomiting, though with a notable incidence of intraoperative right shoulder pain, potentially responsible for conversion to GA. This case series presents an opioid-free scheme of segmental thoracic spinal anesthesia (STSA) with hypobaric ropivacaine, reporting its benefits mainly in terms of shoulder pain occurrence.Patients and Methods: Hypobaric STSA was performed in nine patients undergoing elective LC between May 1 and September 1, 2022. The level of the needle insertion was included between T8 and T9, via a median or a paramedian approach. Midazolam (0.03 mg/kg) and Ketamine (0.3 mg/kg) were used as adjuvants for intrathecal sedation, followed by the administration of hypobaric ropivacaine 0.25% at a dose of 5 mg and then isobaric ropivacaine at a dose of 10 mg. Patients were placed in anti-Trendelenburg position for the entire duration of surgery. LC was conducted through the standard 3 or 4 ports technique with pneumoperitoneum maintained at a pressure of 8– 10 mmHg.Results: Mean patient age was 75.7 (± 17.5) years, with a mean ASA score and Charlson comorbidity index (CCI) of 2.7 (± 0.7) and 4.9 (± 2.7), respectively. STSA was completed without complications in all patients, with no need for conversion to GA. Mean operative time and SA duration were 37.5 (± 8.7) and 145.2 (± 21.8) min, respectively. Intraoperatively, no shoulder or abdominal pain and nausea were reported, with only four and two patients requiring vasopressor and sedative intravenous drugs, respectively. Postoperatively, overall mean VAS pain score and within the first 12 hafter surgery were 3 (± 2) and 4 (± 2), respectively. Median length of stay was 2 (range = 1– 3) days.Conclusion: Hypobaric opioid-free STSA appears to be a promising approach for laparoscopic surgeries, with minimal to null occurrence of shoulder pain. Larger prospective studies are required to validate these findings.Keywords: thoracic spinal anesthesia, laparoscopic cholecystectomy, hypobaric ropivacaine, intrathecal midazolam, intrathecal ketamine

HeartLogic algorithm combines data from multiple implantable defibrillators (ICD)-based sensors to predict impending heart failure (HF) decompensation. A treatment protocol to manage algorithm alerts is not yet known, although decongestive treatment adjustments are the most frequent alert-triggered actions reported in clinical practice. We describe the implementation of HeartLogic for remote monitoring of HF patients, and we evaluate the approach to diuretic dosing and timing of the intervention in patients with device alerts.The algorithm was activated in 229 ICD patients at eight centers. The median follow-up was 17 months (25th-75th percentile: 11-24). Remote data reviews and patient phone contacts were undertaken at the time of HeartLogic alerts, to assess the patient's status and to prevent HF worsening. We analyzed alert-triggered augmented HF treatments, consisting of isolated increases in diuretics dosage.We reported 242 alerts (0.8 alerts/patient-year) in 123 patients, 137 (56%) alerts triggered clinical actions to treat HF. The HeartLogic index decreased after the 56 actions consisting of diuretics increase. Specifically, alerts resolved more quickly when the increases in dosing of diuretics were early rather than late: 28 days versus 62 days, p .001. The need of hospitalization for further treatments to resolve the alert condition was associated with higher HeartLogic index values on the day of the diuretics increase (odds ratio: 1.11, 95% CI: 1.02-1.20, p = .013) and with late interventions (odds ratio: 5.11, 95% CI: 1.09-24.48, p = .041). No complications were reported after drug adjustments.Decongestive treatment adjustments triggered by alerts seem safe and effective. The early use of decongestive treatment and the use of high doses of diuretics seem to be associated with more favorable outcomes.

Paolo Vincenzi,1 Massimo Stronati,2 Paolo Isidori,1 Salvatore Iuorio,2 Diletta Gaudenzi,3 Gianfranco Boccoli,1 Roberto Starnari2 1Department of General Surgery, IRCSS-INRCA, Ancona, Italy; 2Department of Anaesthesiology, IRCSS-INRCA, Ancona, Italy; 3Department of Perioperative Services, AOU “Ospedali Riuniti di Ancona”, Ancona, ItalyCorrespondence: Paolo Vincenzi, Department of General Surgery, IRCSS-INRCA, Via della Montagnola n 81, Ancona, 60127, Italy, Tel + 39 3394578495, Email paolo.vincenzi1981@gmail.comPurpose: Few studies have described segmental thoracic spinal anesthesia (STSA) as primary anesthesiologic method in breast and axillary surgery, documenting the association of intrathecal local anesthetics and opioids. This case series reports an opioid-free scheme of STSA in four elderly patients undergoing major breast and axillary oncological surgery.Patients and Methods: STSA was performed in three female patients undergoing unilateral mastectomy ± axillary lymph node dissection (ALND) or sentinel lymph node biopsy for invasive ductal carcinoma and in one male patient undergoing ALND for melanoma metastases. The level of needle insertion was included between T6-8, via a median or paramedian approach. Midazolam (2 mg) and ketamine (20 mg) were used as adjuvants for intrathecal sedation, followed by the administration of hypobaric ropivacaine 0.25% at a dose of 8 mg. The level of sensory blockade achieved was comprised between C2-3 and T11-12. Postoperative analgesia was maintained through continuous intravenous administration of Ketorolac by an elastomeric pump (90 mg over 24 hrs.).Results: Spinal anesthesia was completed without complications in all patients. Conversion to general anesthesia (GA) and perioperative intravenous sedation were not required. No major postoperative complications and no episodes of postoperative nausea and vomiting (PONV) were reported. No rescue analgesic was administered. All patients were discharged in postoperative day 2 and are alive at 30, 29, 27 and 13 months after surgery, respectively. High grade of satisfaction on the anesthesiologic method was expressed by all cases.Conclusion: STSA with local anesthetic plus midazolam and ketamine might be considered a safe and effective alternative to GA, even in surgeries involving the breast and axillary region, particularly in elderly and frail patients. Larger prospective studies are required to validate these findings.Keywords: spinal anesthesia, breast cancer surgery, axillary surgery, intrathecal midazolam, intrathecal ketamine

The gastrulation process relies on complex interactions between developmental signaling pathways that are not completely understood. Here, we interrogated the contribution of the Hippo signaling effector YAP1 to the formation of the three germ layers by analyzing human embryonic stem cell (hESC)-derived 2D-micropatterned gastruloids. YAP1 knockout gastruloids display a reduced ectoderm layer and enlarged mesoderm and endoderm layers compared with wild type. Furthermore, our epigenome and transcriptome analysis revealed that YAP1 attenuates Nodal signaling by directly repressing the chromatin accessibility and transcription of key genes in the Nodal pathway, including the NODAL and FOXH1 genes. Hence, in the absence of YAP1, hyperactive Nodal signaling retains SMAD2/3 in the nuclei, impeding ectoderm differentiation of hESCs. Thus, our work revealed that YAP1 is a master regulator of Nodal signaling, essential for instructing germ layer fate patterning in human gastruloids.

Extracellular High-mobility group box 1 (HMGB1) contributes to the pathogenesis of inflammatory disorders, including inflammatory bowel diseases (IBD). Poly (ADP-ribose) polymerase 1 (PARP1) has been recently reported to promote HMGB1 acetylation and its secretion outside cells. In this study, the relationship between HMGB1 and PARP1 in controlling intestinal inflammation was explored. C57BL6/J wild type (WT) and PARP1−/− mice were treated with DSS to induce acute colitis, or with the DSS and PARP1 inhibitor, PJ34. Human intestinal organoids, which are originated from ulcerative colitis (UC) patients, were exposed to pro-inflammatory cytokines (INFγ + TNFα) to induce intestinal inflammation, or coexposed to cytokines and PJ34. Results show that PARP1−/− mice develop less severe colitis than WT mice, evidenced by a significant decrease in fecal and serum HMGB1, and, similarly, treating WT mice with PJ34 reduces the secreted HMGB1. The exposure of intestinal organoids to pro-inflammatory cytokines results in PARP1 activation and HMGB1 secretion; nevertheless, the co-exposure to PJ34, significantly reduces the release of HMGB1, improving inflammation and oxidative stress. Finally, HMGB1 release during inflammation is associated with its PARP1-induced PARylation in RAW264.7 cells. These findings offer novel evidence that PARP1 favors HMGB1 secretion in intestinal inflammation and suggest that impairing PARP1 might be a novel approach to manage IBD.

Razionale. L’amiloidosi cardiaca da transtiretina (ATTR–CM), nella sua forma ereditaria o acquisita, è una cardiomiopatia a fenotipo ipertrofico–restrittivo che porta a un‘insufficienza cardiaca progressiva causata dalla deposizione extracellulare di transtiretina. Materiali e Metodi. Presso il nostro centro abbiamo avviato un ambulatorio dedicato alla gestione dei pazienti con amiloidosi cardiaca sin dal 2019. Poiché a quel tempo in Italia non erano disponibili terapie specifiche per questa condizione, decidemmo di creare un protocollo di uso compassionevole per il farmaco tafamidis in base ai risultati dello studio registrativo di fase 3. Risultati. Dopo l‘approvazione del nostro protocollo da parte dell’azienda produttrice e del comitato etico locale, a partire da ottobre 2019 e fino a novembre 2021, sono stati selezionati n=7 pazienti con ATTR–CM i quali erano idonei ricevere il farmaco (tabella 1).Dopo 22 mesi di follow–up, un paziente è deceduto per insufficienza cardiaca avanzata e un paziente ha manifestato insufficienza cardiaca che ha richiesto il ricovero in ospedale. Al termine del nostro protocollo di uso compassionevole non sono state osservate reazioni avverse al farmaco, tutti i pazienti sopravvissuti erano in classe NYHA II e hanno potuto effettuare con successo la transizione alla prescrizione ordinaria secondo i criteri del registro di monitoraggio AIFA (tabella 2). Conclusion i. Il presente rapporto descrive in dettaglio le caratteristiche della prima coorte di pazienti in Italia sottoposta a terapia farmacologica tramite uso compassionevole per il trattamento di ATTR–CM. L‘uso compassionevole è una modalità fattibile ed efficace per avviare la cura farmacologica in pazienti selezionati in attesa dell‘approvazione ufficiale da parte degli enti regolatori, il che può essere molto importante soprattutto nelle malattie ad andamento progressivo, in cui la somministrazione precoce della terapia è fondamentale per ottenere un beneficio clinico significativo.

Introduction Global longitudinal strain (GLS) is a validated and reproducible technique for the measurement of LV longitudinal deformation. There is strong evidence of the prognostic value of GLS in patients with HF and is associated with cardiac mortality independent of clinical and cardiac status. In the present study, we aimed to assess whether GLS can reliably predict prognosis in patients diagnosed with idiopathic inflammatory myopathies. Methods We conducted a prospective observational study enrolling all consecutive patients referred to our clinic between June 2016 and January 2022 with a confirmed diagnosis of IIM and no overt cardiac disease. For each patient, echocardiogram and GLS calculations were done at baseline and at each follow-up. All patients enrolled have been revalued from two to four times during the median 2.5-year follow-up period. Results Forty patients (67% female, mean age 56±12 years) were consecutively enrolled. We detected a significant deterioration of the GLS of the LV (from -19.3±3.6%to -16.8±4.6%; p = 0.006) during the follow-up, while the GLS of the RV was unchanged. We also noticed an increase in the filling pressures as estimated through E/E’, which resulted to be statistically significant (6.5±3.9 to 9.0 ±3.5; p = 0.002), underlying a subclinical diastolic dysfunction of the LV. Traditional markers of systolic dysfunction, such as EF and TAPSE, did not show a significant worsening during the follow-up period. Patients developing a reduction in LV GLS >5% during follow-up experienced an increased incidence of cardiovascular-related death (19% vs 6%; p=0.03). Discussion Cardiovascular manifestations constitute a major cause of death in myositis. Although these complications rarely occur clinically, subclinical manifestations such as conduction disturbances, ventricular dysfunction, myocardial infarction and arrhythmias are often observed. This risk appears to increase especially in the first years after diagnosis. There is therefore a problem of the early recognition of patients who may develop heart disease. Several studies propose to use magnetic resonance imaging as a gold standard to select patients at risk, but its high cost and limited availability make it difficult to use as a screening test. The GLS, consistently with the estimated filling pressures, has demonstrated a high predictive power of cardiovascular-related death in our study, without a modification of the traditional systolic function values. Conclusion The GLS has a high power predictive, it is low cost and highly repeatable, therefore in our opinion, it could play an important role as a screening test in identifying patients with a diagnosis of IIM at higher risk of developing cardiovascular-related death.

Introduction Retinol binding protein (RBP) is a protein synthesized in the liver which forms, along with transthyretin (TTR) the retinol-transport-complex. This complex ligates retinol and thyroxine and transports them in the human plasma. TTR is a protein longer and heavier than RBP. It ligates RBP preventing its renal filtration. Our hypothesis is that the relationship between RBP and TTR is dual: TTR avoids renal filtration of RBP, but also RBP itself, functioning as an endogenous ligand, has an action on TTR by stabilizing and avoiding TTR misfolding. Misfolded TTR proteins form amyloid fibrils rich in beta-cross-sheets that can infiltrate healthy tissues altering their physiology. The infiltration of these fibrils in the cardiac tissue leads to the well-known condition of TTR cardiac amyloidosis (ATTR CA). Our hypothesis is that the lack of TTR stabilization that can happen with low blood levels of RBP is a risk factor for developing ATTR CA. The main goal of our study is to understand if high or normal values of RBP can help exclude any pathological condition linked to the accumulation of misfolded TTR proteins. Methods All patients referred to our Cardiomyopathy Clinic with a clinical and echographic suspicion of CA were consecutively enrolled. All patients underwent a complete diagnostic workup in order to confirm or exclude CA, comprehending lab tests (including RBP4), SPECT, cardiac MR, genetic testing and cardiac biopsy as recommended by current recommendations. At the end of the diagnostic process, patients with ATTR-wt CA were enrolled as cases, and patients with no CA were considered as controls. Patients with ATTR-mutated CA or AL CA were excluded from the present analysis. Results Fifty-nine consecutive patients (42 males, age 77+/-13 years) were enrolled. Of those, 27 had a definitive diagnosis of ATTR-wt CA, while 32 had another diagnosis. Mean levels of RBP4 were not different between patients with and without CA (5.4+/-1.9 vs. 5.0+/-1.8 mg/dl; p=ns) as were Troponin I, BNP and NT-proBNP levels (all p=ns). Among patients with a definitive diagnosis of ATTR-wt CA and a positive SPECT, RBP4 levels were similar between Perugini 2 and 3 scores (5.4+/-2.1 vs. 5.6+/-2.0 mg/dl; p=ns). Discussion From our findings, it seems that there is no significant correlation between low levels of RBP and the presence of ATTR CA as we found no difference in the distribution of RBP levels between cases and controls. It also did not seem to be a useful marker to stratify the levels of myocardial infiltration as long as there is no difference in RBP between Perugini score 2 and 3.

Blood culture negative endocarditis (BCNE) accounts for 5-10% of all cases of endocarditis. The most common cause of this outcome is initiation of antibiotics prior to cultures. The second most common etiology of negative blood culture is infection secondary to intracellular organisms, which require specific serological tests to be detected. Less frequently, the cause BCNE is noninfectious endocarditis. In this case, it could be secondary to systemic inflammatory diseases or malignancies. We present the case of a 64-year-old male who presented to his physician complaining of fever, malaise and generalized weakness. He was treated with oral antibiotics and with evidence of initial improvement, but after a few days the fever recurred. His past medical history was significant for cardiac surgery: he had an aortic bioprosthesis implanted for severe regurgitation secondary to left coronary cusp prolapse. Furthermore, he underwent mitral and tricuspid valve annuloplasty for severe regurgitation secondary to diffuse prolapse of these valves. After recurrence of the fever, he presented to his local hospital. A CT scan was executed and showed left basal lobe hypoattenuation. Given the context, this finding led to a diagnosis of community-acquired pneumonia. He was then treated accordingly and improved. A few days later, the fever returned, and he went back to his local hospital. This time he was visited by a cardiologist, and a transthoracic echocardiogram showed the presence of a vegetation adherent to the aortic bioprosthetic valve. Revising the initial CT scan, the lobar consolidation initially seen was interpreted retrospectively as an atelectasis. On that same day, due to the presence of a painful red eye, the patient was visited by an ophthalmologist. Retinal examination revealed the presence of lesions strongly suggestive of fungal endophthalmitis. Considering these results, fungal endocarditis was suspected. In view of the patient's complexity and the need for a cardiac surgery, the patient was transferred to our hospital and, after performing blood cultures to identify the pathogen, immediately started on an empirical broad-spectrum antibiotic and antifungal therapy. On admission a cerebral CT scan showed the presence of asymptomatic cerebral septic emboli. Due to the presence of cerebral lesions deemed at high hemorrhagic risk, no immediate surgical indication was posed, despite the suspicion of fungal endocarditis. Fortunately, the patient responded to medical treatment alone. However, blood cultures never revealed the presence of a defined pathogen. Therefore, the final diagnosis was that of blood culture negative endocarditis.

Hypertrophic cardiomyopathy (HCM) is a common disease, mostly inherited, with a prevalence of 1:500. Cornerstone of the clinical management of HCM patients is stratifying the risk of sudden cardiac death (SCD) which is the most frightening complication despite its relatively low incidence (0,9% per year). Although mathematical risk scores, as proposed by ESC, are the most used to assess the probability of arrhythmic complications leading to SCD, they have been associated with low sensitivity, precluding some high-risk patients from prophylactic ICD implantation. Among the tools at clinicians’ disposal for risk stratification in HCM patients, the latest AHA/ACC guidelines propose an “individual risk markers strategy”, based on the presence of ≥1 clinical feature such as a family history of SCD, extreme left ventricular hypertrophy (LVH), unexplained recent syncope, NSVT, late gadolinium enhancement (LGE) at CMR, systolic dysfunction and LV apical aneurysm. We present a case that lets us reflect on arrhythmic risk stratification. P.C. is a 58 y.o. male with a history of septal hypertrophy (19 mm) and T wave inversion but without an established diagnosis of HCM. He did not have any familiar history of syncope or SCD. He came to the emergency department for epistaxis and was admitted to the cardiology unit due to the previously mentioned findings, where he underwent cardiac-CTA and CMR showing myocardial bridge of left anterior descending artery, LVH with apical aneurysm and LGE areas localized on the apex (transmural) and on the interventricular septum (subendocardial). No signs of dynamic LVOT obstruction or atrial enlargement emerged from echocardiography. During the observation, asymptomatic NSVT were recorded on continuous ECG monitoring. According to the ESC risk prediction score (3.7%) ICD was not strictly indicated but considering the CMR high-risk profile (according to the suggestions of AHA/ACC) we proposed an ICD implantation anyways. The patient refused any invasive procedure and was implanted with a loop recorder. At 12 months remote monitoring showed a single episode of self-terminated sustained polymorphic ventricular tachycardia (02:23 mm: ss) symptomatic of pre-syncope. The patient was then immediately reached and admitted for ICD implantation in secondary prevention. According to the patient's will, and the no need for bradycardia therapy, an S-ICD was implanted. Figure 1LV apical aneurysm at CMRFigure 2Remote Monitoring

Background Myocardial infarction with non-obstructed coronary arteries (MINOCA) is an increasingly recognized condition with challenging management. Prognosis of this patients could be of concern, in particular for those who experienced recurrent acute myocardial infarction (re-AMI). Moreover, there are limited data on characteristics of re-AMI among MINOCA patients. Methods In this retrospective multicentre cohort study involving seven Hub Hospitals across Italy we enrolled consecutive patients 18 years and older discharged with diagnosis of MINOCA according to the IV universal definition of myocardial infarction who experienced hospitalization for re-AMI during follow-up. Results A total of 54 patients were included (mean age 66±13). Compared to MINOCA patients without re-AMI (n=695), on first angiography MINOCA patients with re-AMI showed less frequently angiographically normal coronaries (37 versus 53%, p=0,032) and had higher prevalence of atherosclerosis involving 3 vessels or left main stem (17% versus 8%, p=0,049). Twenty four patients (44%) with re-AMI underwent a new coronary angiography and 25% had normal coronary arteries, 12% had mild luminal irregularities ( Among patients undergoing new angiography, only 4% had LDL cholesterol under 55 mg/dL, atherosclerosis progression was observed in 11 (46%), 38% received revascularization and 33% experienced a new cardiovascular event (death, AMI, heart failure, stroke) at subsequent follow-up. Conclusions In the present study near one out of two patients with re-AMI after MINOCA showed angiographic atherosclerosis progression requiring revascularization in the majority of cases. These patients rarely presented with recommended LDL cholesterol levels and are at risk for further cardiovascular events, indicating a possible underestimation of cardiovascular risk in this population.

Introduction Cardiac involvement in patients affected by systemic sclerosis is frequent, although mostly asymptomatic, and associated with a negative prognosis. It may be secondary to pulmonary hypertension or defined as an actual systemic-sclerosis related cardiomyopathy, a standalone entity affecting the heart primarily and globally. Speckle-tracking derived global longitudinal strain (GLS) has been proven to be a cost-effective tool in the detection of LV and RV dysfunction in patients with SSc and no overt cardiac disease. The aim of our study was to assess whether GLS can predict clinical outcomes in patients with systemic sclerosis. Methods We conducted a prospective observational study enrolling all consecutive patients referred to our “cardiology clinic for autoimmune diseases and pulmonary hypertension” between June 2016 and January 2022. All patients had a confirmed diagnosis of SSc according to the EULAR guidelines and no overt cardiac disease, pulmonary hypertension, or atrial fibrillation at the time of enrollment. For each patient, echocardiogram and GLS calculations were performed at baseline and at each follow-up. We also collected all data regarding clinical history, hospitalizations or adverse events and ECGs. Results 164 patients (148 female, 58±14 years)were enrolled. 19 (11.6%) patients died during a median follow-up of 3.2 years for mainly non-cardiovascular deaths (7.3%) while cardiovascular deaths were lower (3% non-sudden, 1.3% sudden). Left GLS at first visit was associated with all-cause death, with a 1% left GLS worsening associated with a 19% increased risk of death after adjusting for age, gender, and LVEF (adjusted HR 1.19; 95% CI 1.05-1.35; p=0.007).Similarly, right GLS at first visit was associated with all-cause death, with a 1% right GLS worsening associated with a 12% increased risk of death after adjusting for age, gender, and TAPSE (adjusted HR 1.12; 95% CI 1.03-1.21; p=0.005).Patients with a left GLS worse than -20% had a 3.5-fold increased risk of death when compared to patients with better left GLS (HR 3.55; 95% CI 1.28-9.88; p=0.015). Similarly, patients with a right GLS worse than -20% had a 4.5-fold increased risk of death when compared to patients with better left GLS (HR 4.47; 95% CI 1.4-13.74; p=0.009).Both left and right ventricular GLS were not associated with changes in risk of all-cause hospitalizations, cardiovascular hospitalizations or subsequent diagnosis of pulmonary hypertension. Conclusions GLS is a reproducible, cost effective echocardiographic based method to assess both primary heart disease and its progression. It has proven to be associated with clinical outcomes in patients with systemic sclerosis, therefore allowing a prompt intervention when needed in order to try and prolong the life expectancy of this cohort of patients.

Introduction ST-segment elevation myocardial infarction (STEMI) is one of the most lethal manifestations of ischemic cardiomyopathy. Diagnosis is made through clinical signs, symptoms and, most importantly, the surface ECG. Several conditions mimicking the STEMI repolarization pattern have been hitherto recognised and their identification is of utmost importance in order to provide the correct treatment. Case report A 81-years old man affected by multiple sclerosis and dysphagia was admitted to our hospital for continuous vomiting. His anamnesis was relevant for an episode of bowel obstruction; ECG upon admission exhibited ST-elevation in D1, aVL, V5 and V6 with specular ST-depression in the inferior leads. The patient was unconscious, therefore making it impossible to report any kind of symptoms, in addition, bedside echocardiography showed a thoracic fluid collection completely obscuring cardiac chambers. Physical examination displayed tachypnoea and, most importantly, a tender abdomen with no bowel movements; this specific finding added to the anamnesis and the echocardiography called into doubt the possibility of a real myocardial infarction. Preliminary laboratory findings pointed out high levels of C-reactive protein, procalcitonin and both indirect and direct bilirubin. Being hesitant about the next step, we took a second look at the only clue we had so far, the ECG. At a deeper analysis, the aspects of repolarization did not exactly resemble the convex ST-elevation seen in STEMI presentations, rather reminding (in D1 and aVL) of a pattern called “spiked helmet sign”, described as an index of poor prognosis and increased intrathoracic pressure in critically ill patients. Considered a high suspect of bowel obstruction, a nasogastric tube was placed and, soon after, 3 litres of dark fluid were drained from his stomach. In the following minutes, we witnessed the progressive normalization of the ST alterations initially observed, thus excluding the necessity of a cath lab activation. A CT scan was then performed showing a faecaloma extending from the rectum to the descending colon creating a complete obstruction associated with intestinal pneumatosis and gastric distension. As soon as troponin levels came out normal, the patient underwent surgery, but, unfortunately, he died a few days later due to intervention-related complications. Discussion Although current literature reports several cases of STEMI phenocopies, with a minority referring to bowel obstruction, this is one of the rarely reported circumstances with no instrumental findings or patient symptoms available to support the diagnosis. As most physicians know, diagnoses are rarely straightforward and instrumental findings, especially in the context of an emergency, may drive to incorrect deductions if not properly analysed or incoherent with the clinical context. The “old-fashioned” anamnesis and clinical evaluation may be the keys to unlocking the true diagnosis in difficult contexts where pitfalls can mislead the clinician to the most obvious and quickest conclusion.

Introduction Takotsubo syndrome is a clinical syndrome characterized by typical anamnestic features together with typical ECG and echocardiographic findings. Comparing with the available literature not so many cases of takotsubo syndrome after pacemaker implantation can be found. Furthermore, there are only few articles talking about ECG features in these patient. The case we described allows to observe dynamic ECG alterations in a patient with electro-induced ventriculograms Case Description A 90-year-old male was admitted to the emergency room for important fatigue associated with severe bradycardia (25/min). His cardiovascular history was silent, and his past medical history was characterized by high blood pressure, chronic pulmonary obstructive disease and anemia due to iron deficiency. The ECG showed second degree AVB type 2, with phases of 2:1 AVB and paroxysmal third degree AVB on continuous monitoring. The routine blood tests showed normal T troponin and BNP was 420 pg/mL. The echocardiogram revealed normal biventricular dimensions and systolic function with moderate aortic valve stenosis. The patient underwent urgent permanent DDD pacemaker implantation without previous isoproterenol administration. During the procedure he referred important pain on the site of the wound, and he became confused and agitated. The procedure was complicated by massive pneumothorax that needed quick decompression. On the 2nd day after pacemaker implantation the ECG revealed electro-induced atrium-guided ventriculograms and began to modify with only mild ST-segment elevation in V2 and initial T-wave inversion from V3 to V6 and in I - II - aVF. On the next days, T-waves became deeper and QTc prolonged to 540 ms. These abnormalities were then gradually resolved on the 11th day. Mild transient attenuation of the amplitude of the QRS complexes in V2 – V3 leads on day 1 could be reported. Another echocardiogram was then performed, which showed new apical akinesis with “apical ballooning” aspect and EF of 40%. TnT and BNP values increased. Coronary angiogram was not performed due to patient rejection, so that coronaropathy could not be excluded with certainty. Nevertheless, the patient had only high blood pressure as cardiovascular risk factor and that the probability of the diagnosis of takotsubo cardiomyopathy was assessed of 76,9% by InterTAK diagnostic score, so that we considered Takotsubo syndrome the most likely diagnosis. Therefore, the patient's therapy was then optimized with an increase in the dosage of ACE inhibitors. At one month follow-up the ECG remained stable, and the echocardiogram showed a preserved ejection fraction (EF = 55%), without alterations of the segmental contractility. BNP and TnT values were normal. Therapy was left unmodified. Conclusions Takotsubo syndrome should be consider a rare but possible complication of pacemaker implantation. This is true especially for patients affected by frailty and cognitive impairment. There are no specific ECG criteria for takotsubo syndrome in patients with electro-induced ventriculograms, but anomalies of the repolarization are similar to those in patients with spontaneous ventricular activity. Transient attenuation of the QRS complexes voltages could be seen even just in the precordial leads and it is generally present in the very acute phase.

Introduction Sacubitril/valsartan (ARNI) has demonstrated a significant benefit compared to angiotensin inhibitor (enalapril) in decreasing both morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF). While. recent studies demonstrated that in HFrEF patients, ARNI decreased ventricular arrhythmias no data is available with regards to the supraventricular arrhythmic burden in HFrEF patients with an implantable cardioverter defibrillator (ICD) or cardiac resynchronisation therapy-defibrillator (CRT-D) and remote monitoring. The aim of out study was to assess if ARNI therapy was able to significantly reduce supraventricular arrhythmias. More specifically the primary endpoint was the incidence of AT/AF episodes, as detected by the device. Secondary endpoints included the total burden of AT/AF, the mean number of premature ventricular contractions (PVC) per hour and the percentage of biventricular pacing per day (in patients with CRT-D). Methods We conducted a multicentre, observational, prospective registry : the SAVE THE RHYTHM (SAacubitril Valsartan rEal-world registry evaluating THE arRHYTHMia burden in HFrEF patients with implantable cardioverter defibrillator). We enrolled all patients with HFrEF, ICD or CRT-D actively followed through remote monitoring and starting treatment with sacubitril/valsartan. All patients were followed-up for at least one year. Results At the end of enrollment, 265 patients from 5 centres had at least one sacubitril/valsartan prescription (88% males, age 68±10 years). The annual incidence of AT/AF episodes decreased from 16.6% before sacubitril/valsartan to 12.8%, 6.7% and 0.7% according to the maximum tolerated dose (24/26 mg, 49/51 mg and 97/103 mg, respectively; p=0.026). After treatment with sacubitril/valsartan, patients with at least one episode of AT/AF decreased from 32.6% to 26.5% (24/26 mg), 24.3% (49/51 mg) and 6.9% (97/103 mg); p=.041. A significant decrease in the number of PVC (-28 per hour) and in the rate of appropriate shock (-0.8% per year) were seen in patients with a previous diagnosis of paroxysmal or persistent AF. Patients with permanent AF (n=7) experienced no benefits from sacubitril/valsartan therapy in terms of arrhythmic burden reduction. Patients with a CRT device (41%) experienced a significant increase in biventricular pacing time (+3% per day). Discussion Therapy with sacubitril/valsartan could decrease arrhythmic burden in patients with non-permanent AF and HFrEF and reduce subclinical supraventricular arrhythmias in patients with no history of AF.

Background left ventricular non-compaction (LVNC) cardiomyopathy is an often underdiagnosed and under-classified disease deriving from the incomplete development of ventricular myocardium. Clinical presentations may be variable and uncommon, ranging from an apparent lack of functional anomalies to heart failure, ventricular arrhythmias and, in some cases, even ischemic stroke. Despite great improvements in diagnostic performance there is still a widespread lack of evidence regarding the prognosis and management of affected patients. Methods all consecutive patients admitted to our Cardiology Institution from October 2009 to August 2022 fulfilling LVNC criteria by echocardiography or cardiovascular magnetic resonance (CMR) or both, were consecutively enrolled. CMR has been performed wherever possible. All patients underwent a complete cardiological visit, a 12-lead ECG and echocardiography at baseline, whereas at follow-up, if a complete visit was not possible, information regarding patients’ endpoints was acquired through telephonic contact. Additional diagnostic exams or implantation of a cardiac device were also performed if indicated. The primary endpoint was a composite of at least one between: sustained ventricular arrhythmias, an appropriate ICD intervention and sudden cardiac death. Secondary endpoints included supraventricular arrhythmias, unplanned cardiac hospitalizations, acute decompensated, chronic heart failure and ischemic stroke. Risk predictor analyses were not performed as the overall event rates were low and the risk for type II error was high. Results forty patients (26 males; age 45±17) were prospectively enrolled and followed up for a median of five years. CMR and echocardiography were overall agreeing on the majority of the diagnoses, with 62.5% of patients meeting the echo criteria and 70% of patients meeting the CMR criteria for LVNC. The incidence of the primary endpoint was 1.8% per years. Male gender and late gadolinium enhancement (LGE) were correlated with an increased incidence of the primary endpoint, while LVEF, NC/C or functional status were not associated with a significantly increased risk of the composite endpoint. HF diagnosis was the most common endpoint (6.1% annual incidence). The annual incidence of supraventricular arrhythmias was 3.0% and the annual incidence of stroke was 0.7%. Twenty-four patients (60%) experienced at least one hospitalization during follow-up. Unplanned hospitalizations represented 20% of all hospitalizations and were mainly HF-related. Planned hospitalizations were performed for elective procedures such as atrial fibrillation cardioversion, ablation, coronary angiography or diagnostic check-ups. Discussion in patients with LVNC, there is an increased incidence of cardiac-related outcomes than in the general population; furthermore, male gender and myocardial fibrosis are associated with increased risk of events. This trend highlights the importance of a prompt diagnosis and, obviously, of a correct knowledge of such disease.

Propofol infusion syndrome (PRIS) is a rare but potentially lethal side effect of propofol. In most cases it shows various combinations of signs such as unexplained metabolic acidosis, rhabdomyolysis, hepatomegaly, renal failure, hypertriglyceridemia, malignant arrhythmia and rapidly progressive cardiac failure. The development of coved ST elevation in the right precordial leads of the electrocardiogram (ECG), similar to that seen in the type I Brugada syndrome may be the first sign of cardiac instability. There is no specific treatment for PRIS. Successful management consists of an early recognition of its signs followed by a prompt propofol infusion termination. We present the case of a 35-year-old male affected by mild hypertension. He was found by his wife during a transitory loss of consciousness episode. He had resulted positive to Sars Cov 2 infection a day before and was symptomatic for fever and myalgia. An ambulance was immediately called and the patient was transferred to the emergency department for a suspected out-of-hospital-cardiac arrest. The initial one-lead ECG performed by the emergency physician was unremarkable. On arrival he was in a coma state but with stable hemodynamics. ECG showed only an asymmetric T wave inversion in V4-V6 leads. The cardiac echocardiogram did not show any major alterations. In the meantime, due to worsening of respiratory function, orotracheal intubation was performed and the patient was sedated with propofol, midazolam and fentanyl. Subsequently, an episode of atrial fibrillation was documented. Amiodarone infusion was started and the patient reverted to sinus rhythm after a few hours. The following day two episodes of Torsade de Pointes during prolonged QTc (660 ms) occurred. These arrhythmias were treated successfully with magnesium sulfate infusion. Blood analysis showed severe hypokalemia that was immediately corrected. After the hemodynamic stabilization the ECG showed a pattern highly resembling the Brugada pattern type 1 in the right precordial leads. Moreover CPK, myoglobin, high sensitivity troponin I levels started to rise, along with creatinine, triglycerides and markers of hepatic injury. Propofol had been administered continuously for eight days, so PRIS was suspected as the primum movens of this clinical scenario. Propofol infusion was immediately interrupted. Thereafter, the patient gradually improved and was extubated. As soon as the patient's hemodynamic conditions allowed it, a coronary CT and a cardiac MRI were performed, but were unremarkable. To further evaluate the case, a flecainide challenge test was performed, but no significant ECG change was induced. Nonetheless, given both the history of ventricular arrhythmia, the young age of the patient and the unexplained transitory loss of consciousness a subcutaneous defibrillator was implanted as a form of secondary prevention.