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The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular hypertrophy in the absence of abnormal cardiac loading conditions. This “umbrella diagnosis” includes the “classic” hypertrophic cardiomyopathy (HCM), due to sarcomere protein gene mutations, and its phenocopies caused by intra‐ or extracellular deposits, such as Fabry disease (FD) and cardiac amyloidosis (CA). All these conditions share a wide phenotypic variability which results from the combination of genetic and environmental factors and whose pathogenic mediators are poorly understood so far. Accumulating evidence suggests that inflammation plays a critical role in a broad spectrum of cardiovascular conditions, including cardiomyopathies. Indeed, inflammation can trigger molecular pathways which contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation, and microvascular dysfunction. Growing evidence suggests that systemic inflammation is a possible key pathophysiologic process potentially involved in the pathogenesis of cardiac disease progression, influencing the severity of the phenotype and clinical outcome, including heart failure. In this review, we summarize current knowledge regarding the prevalence, clinical significance, and potential therapeutic implications of inflammation in HCM and two of its most important phenocopies, FD and CA.

Background In the acute management of ST-elevation myocardial infarction (STEMI), glycoprotein IIb/IIIa inhibitors (GPIs) bolus not followed by intravenous infusion is potentially advantageous given their fast onset and offset of action, but clinical evidence in a contemporary setting is limited. Methods We collected data from consecutive STEMI patients admitted to the cardiac catheterization laboratory of the Fondazione Policlinico Universitario A. Gemelli from October 2017 to September 2019. Results Out of 423 consecutive STEMI patients, 297 met the inclusion and exclusion criteria and were included in the study. Of them, 107/297 (36%) received an intracoronary GPI bolus-only during primary percutaneous coronary intervention (PPCI) not followed by intravenous infusion and 190/297 (64%) received standard antithrombotic therapy. Of the 107 GPI-treated, 22/107 (21%) had P2Y12 inhibitor pre-treatment (adjunctive strategy) and 85/107 (79%) did not (bridging strategy). During hospital staying, there was no difference in the primary safety endpoint of TIMI major+minor bleeding (p=0.283), TIMI major (p=0.267) or TIMI minor (p=0.685) bleeding between groups. No stroke event occurred in the GPI group. Despite patients receiving GPI having a significantly higher intraprocedural ischemic burden, no significant differences were found in the efficacy outcomes between groups. Consistent findings were observed for patients receiving GPIs bolus before (bridging strategy) or after (adjunctive strategy) P2Y12 inhibitors, compared to those receiving standard therapy. Multivariate logistic regression analyses did not find any independent predictors significantly associated to the primary and secondary composite endpoints. Conclusions In a contemporary real-world population of STEMI patients undergoing PPCI, the use of intracoronary GPIs bolus-only in selected patients at high ischemic risk is safe and could represent a useful antithrombotic strategy both in those pre-treated and in those naive to P2Y12 inhibitors.

Wall shear stress (WSS) is involved in coronary artery plaque pathological mechanisms and modulation of gene expression. This study aims to provide a comprehensive haemodynamic and biological description of unstable (intact-fibrous-cap, IFC, and ruptured-fibrous-cap, RFC) and stable (chronic coronary syndrome, CCS) plaques and investigate any correlation between WSS and molecular pathways.We enrolled 24 CCS and 25 Non-ST Elevation Myocardial Infarction-ACS patients with IFC (n = 11) and RFC (n = 14) culprit lesions according to optical coherence tomography analysis. A real-time PCR primer array was performed on peripheral blood mononuclear cells for 17 different molecules whose expression is linked to WSS. Computational fluid dynamics simulations were performed in high-fidelity 3D-coronary artery anatomical models for three patients per group. A total of nine genes were significantly overexpressed in the unstable patients as compared to CCS patients, with no differences between IFC and RFC groups (GPX1, MMP1, MMP9, NOS3, PLA2G7, PI16, SOD1, TIMP1, and TFRC) while four displayed different levels between IFC and RFC groups (TNFα, ADAMTS13, EDN1, and LGALS8). A significantly higher WSS was observed in the RFC group (p 0.001) compared to the two other groups. A significant correlation was observed between TNFα (p 0.001), EDN1 (p = 0.036), and MMP9 (p = 0.005) and WSS values in the RFC group.Our data demonstrate that IFC and RFC plaques are subject to different WSS conditions and gene expressions, suggesting that WSS profiling may play an essential role in the plaque instability characterization with relevant diagnostic and therapeutic implications in the era of precision medicine.

Aims Adenosine has been tested in several randomized controlled trials (RCTs) to minimize the incidence of coronary microvascular obstruction (CMVO). The aim of this study was to pool all the RCTs comparing intracoronary or intravenous adenosine versus placebo in patients with acute coronary syndrome (ACS) undergoing myocardial revascularization. Methods and results PubMed and Scopus electronic databases were scanned for eligible studies up to 5th June 2022. A total of 26 RCTs with 5843 patients were included. Efficacy endpoints were major adverse cardiac events (MACE), all-cause death, non-fatal myocardial infarction, and heart failure. Atrioventricular blocks and ventricular fibrillation/sustained ventricular tachycardia (VF/SVT) were the safety endpoints. Myocardial blush grade, thrombolysis in myocardial infarction (TIMI) flow grade, left ventricular ejection fraction (LVEF), infarct size, and ST-segment resolution were also assessed. Adenosine administration was not associated with any clinical benefit in terms of MACE, all-cause death, non-fatal myocardial infarction, and heart failure. However, adenosine was associated with an increased rate of advanced atrioventricular blocks and of VF/SVT in studies with total mean ischaemic time >3 h, compared to placebo. Remarkably, among patients undergoing percutaneous coronary intervention, adenosine was associated with reduced myocardial blush grade 0–1 and TIMI flow grade 0–2, compared to placebo. Furthermore, adenosine did not show favourable effects on LVEF and infarct size. Conclusion Adenosine infusion, as adjunctive therapy in ACS, was associated with an increased risk of advanced atrioventricular blocks and increased rates of adenosine-triggered ventricular arrhythmias in patients with long ischaemic time, without providing any clinical benefit compared to placebo.

Summary Background Atrial fibrillation is the most common complication after cardiac surgery and is associated with extended in-hospital stay and increased adverse outcomes, including death and stroke. Pericardial effusion is common after cardiac surgery and can trigger atrial fibrillation. We tested the hypothesis that posterior left pericardiotomy, a surgical manoeuvre that drains the pericardial space into the left pleural cavity, might reduce the incidence of atrial fibrillation after cardiac surgery. Methods In this adaptive, randomised, controlled trial, we recruited adult patients (aged ≥18 years) undergoing elective interventions on the coronary arteries, aortic valve, or ascending aorta, or a combination of these, performed by members of the Department of Cardiothoracic Surgery from Weill Cornell Medicine at the New York Presbyterian Hospital in New York, NY, USA. Patients were eligible if they had no history of atrial fibrillation or other arrhythmias or contraindications to the experimental intervention. Eligible patients were randomly assigned (1:1), stratified by CHA2DS2-VASc score and using a mixed-block randomisation approach (block sizes of 4, 6, and 8), to posterior left pericardiotomy or no intervention. Patients and assessors were blinded to treatment assignment. Patients were followed up until 30 days after hospital discharge. The primary outcome was the incidence of atrial fibrillation during postoperative in-hospital stay, which was assessed in the intention-to-treat (ITT) population. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT02875405, and is now complete. Findings Between Sept 18, 2017, and Aug 2, 2021, 3601 patients were screened and 420 were included and randomly assigned to the posterior left pericardiotomy group (n=212) or the no intervention group (n=208; ITT population). The median age was 61·0 years (IQR 53·0–70·0), 102 (24%) patients were female, and 318 (76%) were male, with a median CHA2DS2-VASc score of 2·0 (IQR 1·0–3·0). The two groups were balanced with respect to clinical and surgical characteristics. No patients were lost to follow-up and data completeness was 100%. Three patients in the posterior left pericardiotomy group did not receive the intervention. In the ITT population, the incidence of postoperative atrial fibrillation was significantly lower in the posterior left pericardiotomy group than in the no intervention group (37 [17%] of 212 vs 66 [32%] of 208 [p=0·0007]; odds ratio adjusted for the stratification variable 0·44 [95% CI 0·27–0·70; p=0·0005]). Two (1%) of 209 patients in the posterior left pericardiotomy group and one ( Interpretation Posterior left pericardiotomy is highly effective in reducing the incidence of atrial fibrillation after surgery on the coronary arteries, aortic valve, or ascending aorta, or a combination of these without additional risk of postoperative complications. Funding None

Background Transcatheter aortic valve implantation (TAVI) in the treatment of severe aortic stenosis has considerably grown in the latest years. There are limited data, however, about predictors of long-term prognosis in this population. Particularly, whether arrhythmic burden is associated with clinical outcome has poorly been investigated. Methods We performed 24-hour 3-channel ECG Holter recording (HM) in 284 consecutive patients who underwent TAVI for severe aortic stenosis at our Center within 30 days from a successful procedure (average 10.2 days, range 2-30). For each patient we obtained the number of premature ventricular complexes (PVCs) and the presence of non-sustained ventricular tachycardia (NSVT, ≥3 PVCs with a rate ≥100 bpm). Assessment of clinical events at follow-up was performed by clinical visits or telephone interview of patients or relatives (in case of fatal events). The primary end-point of the study was a composite of cardiovascular death and resuscitation from cardiac arrest (CVE); total mortality was assessed as secondary end-point. Results Frequent PVCs (≥30/hour) and episodes of NSVT were found in 49 (20.2%) and 52 (21.4%) patients, respectively. Clinical outcome was obtained for 243 patients (85.6%). At an average follow-up of 3.5 year (range 1.0-8.6), CVE occurred in 25 patients (8.8%) and 64 died (22.5%). Frequent PVCs at HM were detected in 11/25 (44.0%) and 38/218 (17.4%) patients with and without CVE, respectively (p=0.006). Episodes of NSVT were detected in 9/25 (36.0%) and 43/218 (19.7%) patients with and without CVE, respectively (p=0.07). Furthermore, frequent PVCs were present in 18/64 (28.1%) and 31/179 (17.3%) patients dead and alive, respectively (p=0.07), whereas NSVT episodes were detected in 17/64 (26.6%) and 35/179 (19.6%) patients dead and alive, respectively (p=0.29). Frequent PVCs maintained independent association with CVE after correction for confounding variables at multivariable analysis (HR 2.63; 95 CI 1.05-6.62; p=0.04). Conclusions Our data indicate that assessment of ventricular arrhythmic burden after TAVI is helpful to identify patients at increased risk of cardiovascular death/cardiac arrest during medium follow-up.

Background Percutaneous coronary intervention (PCI) is the milestone of treatment for patients with acute coronary syndrome (ACS). However, a considerable number of patients do not achieve a complete myocardial reperfusion since coronary microvascular obstruction (CMVO) might occur. Adenosine is one of the pharmacological strategies tested in several randomized controlled trials (RCTs) to minimize the incidence of CMVO. However, conflicting results have been reported so far. The aim of the present study was to evaluate all the RCTs comparing intracoronary or intravenous adenosine versus placebo as adjunctive therapy in patients with ACS undergoing PCI or thrombolysis. Methods PubMed and Scopus electronic databases were scanned for eligible studies up to June 5th, 2022. Our meta-analysis included 26 randomized RCTs with a total of 5843 patients involved. Primary endpoints were the rate of clinical events, defined as major adverse cardiovascular events (MACE), heart failure (HF), all-cause-death and non-fatal myocardial infarction (MI). The rate of advanced atrioventricular (AV) blocks and ventricular fibrillation/sustained ventricular tachycardia (VF/SVT) were considered as safety endpoints. Further subgroup analyses and meta regressions were conducted to evaluate the role of different procedural and non-procedural factors influencing the results. Finally, a secondary analysis was conducted only including RCTs enrolling patients with ST-segment elevation myocardial infarction (STEMI). Results Adenosine administration did not confer any significant clinical benefit in terms of reduction of MACE (RR 0.91 CI 0.79-1.05, p 0.16), all-cause-death (RR 0.90 CI0.74-1.09, p 0.28), non-fatal MI (RR 1 CI 0.74 - 1.35, p 0.44) and HF (RR 0.94 CI 0.77-1.16, p 0.59). Remarkably, adenosine was associated with a significant reduction of post-procedural CMVO parameters such as Myocardial Blush Grade (MBG) 0-1 (RR 0.69 CI 0.53-0.90, p 0.01) and Thrombolysis In Myocardial Infarction (TIMI) flow grade 0-2 (RR 0.67 CI 0.53-0.85, p 3 hours (RR 1.67 CI 1.14-2.42) Conclusions This is the most up-to-date meta-analysis summarizing the available evidence on adenosine safety and efficacy in the prevention or treatment of CMVO in ACS patients. Although adenosine improves surrogate parameters of myocardial perfusion, its use does not provide any clinical benefits. Additionally, adenosine infusion increases the risk of advanced AV blocks. Moreover, a longer ischemic time seems to be associated with a higher rate of adenosine-triggered ventricular arrhythmias, suggesting that higher myocardial ischemic damage may represent a substrate for adenosine arrhythmogenic effects.

Background Heart failure with preserved ejection fraction (HFpEF) represents nowadays the most frequent presentation of heart failure (HF) in patients aged > 65 years. The underlying reason for the failure of the vast majority of randomized controlled trials (RCTs) in HFpEF patients has been identified in the heterogeneity of pathophysiology and clinical phenotype of this clinical syndrome. Coronary microvascular dysfunction (CMD) represents one among various pathophysiological mechanisms, together with pulmonary vascular disease, pericardial restraint, impaired chronotropic reserve and abnormal autonomic tone. Whether CMD-HFpEF endotype differs from the others in terms of echocardiographic parameters and clinical outcomes is still a matter of debate. Therefore, a systematic review and meta-analysis were performed in order to compare HFpEF populations with or without CMD in terms of echocardiographic features and clinical outcomes. Methods We searched for articles published in PubMed, Scopus and Wiley comparing HFpEF population with or without CMD up to 1st September 2022. Observational studies, reporting echocardiographic parameters mentioned in HFA-PEFF score and/or clinical time to event data, were included. E/e’ ratio, left atrial volume index (LAVi) and left ventricular mass index (LVMi) constituted our three parameters of choice and Hedge's g was the summary effect size. The composite of HF hospitalization and all-cause death represented our clinical endpoint. Meta-regressions according to follow-up time were performed in order to explore potential heterogeneity sources across studies. Results We identified 9 prospective observational studies, enrolling 797 patients with HFpEF. On pooled analysis, patients with CMD present a more severe echocardiographic phenotype, determined by a higher LAVi [effect size (ES) 0.40; Confidence Interval (CI) 0.11, 1.69], E/e’ ratio (ES 0.65; CI 0.28, 1.02) and LVMi (ES 0.27; CI 0.01, 0.53) compared to no-CMD patients. Furthermore, CMD patients showed a significant higher rate of the composite endpoint of all-cause-death and hospitalization for HF (HR 3.22, CI 1.2-8.5, p 0.02). At meta-regression, a significant correlation was found between logarithmic hazard ratios and follow-up time reported (z=2.03, p value 0.04), suggesting that long-term follow-up of CMD-HFpEF patients is required to track the natural trajectory of the disease. Conclusions Aside from being considered a pathophysiological hallmark in the development of HFpEF, CMD seems to play an aggravating role in the progression of the disease, leading both to more severe echocardiographic parameters and worse clinical outcomes compared to other endotypes. Thus, different echocardiographic thresholds could allow for a better prognostic stratification and for identifying the subset of patients who deserve a CMD assessment and who are eventually more likely to benefit from drugs targeting CMD.

Background Chronic coronary total occlusions (CTO) are considered an emerging predictor of ventricular arrhythmias (VAs) but currently there are only few data on arrhythmic outcomes in patients affected by CTO undergoing radiofrequency catheter ablation of VAs. Objective This study sought to evaluate the impact of unrevascularized CTO on the recurrence of VAs after catheter ablation. Methods This was a single-center retrospective study that enrolled 120 patients, between 2015 and 2020. All patients were admitted for ventricular tachycardia (VT) or high premature ventricular contractions (PVCs) burden (>25% detected by Holter ECG), without evidence of acute coronary syndrome; they underwent coronary angiography, electrophysiology (EP) study and three-dimensional electroanatomic mapping (3D-EAM) followed by VAs ablation. Results Twenty-eight patients (23%) of 120 patients showed CTO at coronary angiography. At baseline, CTO group presented with higher prevalence of hypertension, chronic renal disease, systolic ventricular dysfunction, secondary prevention ICD implantation, higher rate of low abnormal activities by 3D-EAM compared to the non-CTO group. At a median follow-up of 15 months (range 1-96 months) after catheter ablation, the only independent predictor of VAs recurrence was the presence of moderate to severe left ventricular (LV) dysfunction (p=0.02). Conclusion The presence of CTO does not predict VAs recurrence after catheter ablation which is instead predicted by LV dysfunction.

Background and aims Worldwide, air pollution is the fourth leading cause of death. Both brief and long-term exposures to air pollution have been associated with marked increases in cardiovascular-related morbidity and mortality. Previous studies have focused on the short-term influence of particulate pollutants on ventricular arrhythmia (VA) development, primarily expressed as 24-hour Holter ECG monitoring arrhythmic burden or as presentation as life-threatening ventricular arrhythmias. The aim of our study was to investigate the association between air pollutant exposure and VA burden in remotely-monitored patients. Methods We enrolled retrospectively 86 patients carriers of implantable cardioverter-defibrillators (ICD), loop recorders (ILR) or pacemaker devices with remote monitoring via CarelinkTM Medtronic or Merlin.netTM PCN Abbott softwares. Intracavitary and ILR tracings were reviewed by EP personnel at our centre to define VA burden and the number of appropriate shocks and ATPs occurred in 2021. Demographic and clinical characteristics (e.g. cardiovascular history, ejection fraction, smoking, antiarrhythmic drugs (AADs)) were collected through telephone interviews. Each patient's residential and working address were used to obtain information on pollutant exposure in the years 2017-2021 in terms of annual mean concentrations of PM10, PM2.5, ozone, sulfur dioxide, carbon dioxide, carbon monoxide and benzene, as determined by European Environmental Agency air quality reports. The primary endpoint was a composite of ventricular fibrillation, sustained and nonsustained ventricular tachycardia, appropriate ATP or shocks in patients with various levels of air pollutants exposure. Results Of 86 patients (58 male, mean age 63.2±18.7 years) enrolled in this study, 44 (51.6%) had received an ICD, 32 of whom (37.2%) with a primary prevention indication. 31 patients (36.1%) had been receiving at least one AAD. History of coronary artery disease (CAD) was present in one third of the study population and baseline mean EF was 49.8±13.8%. VA events occurred in 17 patients (19.8%), all with a significantly lower baseline EF (40.3±12.2% vs 51.5±13.5% p=0.005). Average mean values of benzene concentration in the previous 4 years were significantly higher in patients suffering from a VA event (1.64±0.82 μg/m3 vs 1.12±0.48 μg/m3, p=0.001), as were PM2.5 values (11.64±1.98 vs 10.74±1.28 μg/m3, p=0.023). A weak but positive correlation was found between median PM2.5 concentration, benzene and VAs (p=0.023, p=0.001 respectively). A multivariate regression model was built, including long-term exposure to benzene and PM2.5 and baseline EF, and it would explain 29.8% of the variance in VAs, correctly classifying 78.1% of cases. Conclusions This study was the first to evaluate the relationship between long-term exposure to a wide array of air pollutants and VAs in a European population. In our sample, we found a weak but significant correlation between a higher chronic exposure to benzene and recorded VA events. Possible mechanisms may include oxidative stress and a direct, nonspecific membrane action due to benzene lipophilic properties. Hence, we highlighted the possible role of outdoor benzene exposure in ventricular arrhythmogenesis for the first time, a finding that requires validation through subsequent studies aimed at elucidating the role of air pollution as a ubiquitous, potentially modifiable, population-based risk factor.

Introduction Atherosclerotic plaque healing is a dynamic process that promotes plaque repair after destabilization. Previous studies showed that healed plaques are more common in patients with chronic coronary syndrome than in those with acute coronary syndrome, suggesting that they might be a marker of clinical stability. The mechanisms underlying plaque healing are not completely understood. The aim of the present study was to evaluate sex-based differences in plaque phenotype and healing of non-culprit coronary lesions by optical coherence tomography. Methods In this observational, single-center cohort study, we enrolled patients from the OCT Registry of the Fondazione Policlinico A Gemelli IRCCS. A total of 205 patients with both acute coronary syndromes or chronic coronary syndromes undergoing coronary angiography and intravascular OCT imaging of non-culprit vessels were included in the analysis and divided into two groups according to gender. Results Of 205 patients, 153 were male (75%) and 52 (25%) female. Compared with male patients, female patients had lower prevalence of lipid-rich plaque (40.4% vs. 57.7%; p=0.030), plaque rupture (7.7% vs. 21.2%; p=0.028) and cholesterol crystal (13.5% vs. 29.5%; p=0.022). Mean lipid arc and calcium depht were significantly lower in female patients than in male ones (118.0° ± 79.9° vs. 135.5° ± 77.9°; p=0.011; and 52.7 µm ± 79.2 µm vs. 72.3 µm ± 93.5 µm; p=0.007) while fibrous cap tended to be thicker (108.2 µm ± 70.4 µm vs. 96.2 µm ± 72.9 µm; p=0.055). Healed plaques were significantly more frequent in female patients than in male patients (51.9% vs 34.6%; p = 0.027). The prevalence of fibrous plaque, thrombi, neovascularization, diffuse calcifications and spotty calcification was not different between the two groups. Conclusion Females have a distinct atherosclerotic phenotype and healing capacity compared with male patients, including lower prevalence of lipid-rich plaque, cholesterol crystals and plaque ruptures and higher prevalence of healed plaques in non-culprit coronary lesions.

Introduction and objectives The clinical value of ECG repolarization parameters associated with ventricular arrhythmias (VAs) in Takotsubo syndrome is still under debate. We aimed to evaluate ECG predictors of subacute VAs, defined as those occurring after the first 48 hours from admission. Methods This is a single-center observational study enrolling patients admitted to the Cardiology Department between 2012 and 2018 with confirmed diagnosis of Takotsubo syndrome. Data collection included a 12-lead ECG on admission and at 48 hours, continuous telemetry monitoring, blood testing, transthoracic echocardiography and coronary angiography during hospitalization. VAs events were defined as: premature ventricular contractions ≥2000 within a 24-hour window of telemetry monitoring, ventricular fibrillation, sustained ventricular tachycardia (VT), polymorphic VT and non-sustained VT. Results A total of 87 patients (age 72±12 years old) were enrolled. During an average of 16±14 days of hospitalization, subacute VAs were documented in 22 patients (25%) after 127±75 hours from admission. Subacute VAs were associated with an increased in-hospital mortality (p=0.030). The corrected global (mean of the 12-lead ECG values) Tpeak-Tend interval at 48 hours from admission was an independent predictor of subacute VAs. The corrected global Tpeak-Tend was statistically superior to the standard corrected QT interval to predict subacute VAs (Z test, p=0.040). A cut-off of 108 msec for the corrected global Tpeak-Tend yielded a 71% sensitivity and 72% specificity for subacute VAs. Conclusions In patients with Takotsubo syndrome subacute VAs are associated with repolarization alterations that can be identified on the conventional ECG using the Tpeak-Tend interval.

Background Takotsubo syndrome (TTS) is burdened by a not negligible rate of an impaired short-term prognosis. Current existing models, based on classical statistical methods, showed only moderate accuracy to predict the risk of in-hospital adverse events following admission for TTS. We sought to design a machine-learning (ML) based model to predict the risk of in-hospital death among patients admitted for TTS, and to provide clusters of TTS patients associated with different risks of adverse short-term prognosis. Methods A Penalized Logistic Regression-based ML model for predicting in-hospital death was trained and tested on a cohort of 3482 patients with TTS from the international, multicenter, InterTAK Registry. 33 clinically relevant variables were selected to be included in the prediction model. Model performance was assessed according to area under the receiver operating characteristic curve (AUC). A K-Means clustering algorithm was designed to stratify patients into phenotypic groups based on the most relevant features emerging from the main model. Results The overall incidence of in-hospital death was 5.2%. The InterTAK-ML model showed an AUC of 0.88 (95%CI 0.87-0.90) and 0.87 (95%CI 0.83-0.91) with respect to in-hospital death prediction in the train and test cohorts, respectively. By exploiting the 5 variables showing the highest feature importance (use of catecholamines, type of triggering factor, left ventricular ejection fraction, white blood cell count, heart rate), TTS patients were clustered into five groups associated with different risks of in-hospital death (29.4% vs 3.9% vs 1.6% vs 1.3% vs 0.7%). Conclusion A ML-based approach for the identification of TTS patients at risk of adverse short-term prognosis is feasible and effective. The InterTAK-ML model showed accurate discriminative capability for the prediction of in-hospital death. To support clinical decision-making, TTS patients can be clustered into groups entailing different risks of death based on routinely collected variables.

Left ventricular (LV) hypertrophy is the main feature of Fabry cardiomyopathy (FC), but the right ventricle (RV) is also frequently affected. Previous studies failed to demonstrate an independent association between RV hypertrophy or conventional parameters of RV function and the occurrence of adverse outcomes in patients with FC. Nevertheless, if RV free wall strain (RV-FWS), assessed by 2D speckle tracking analysis, may provide a better prognostication is currently unexplored. We retrospectively evaluated the association between RV-FWS and the occurrence of cardiovascular events in a cohort of 28 patients with FC. The study endpoint comprises the occurrence of cardiovascular mortality, severe heart failure symptoms, new-onset atrial fibrillation, bradyarrhythmias requiring pacemaker implantation and sustained ventricular tachyarrhythmias. The median value of RV-FWS was 21.4% (interquartile range:17.1-23.9%) and a total of 18 (64%) patients showed reduced RV-FWS ( In Conclusion, impaired RV-FWS was not independently associated with the occurrence of cardiovascular events in FC, confirming previous observations that prognosis is mainly driven by the severity of LV cardiomyopathy.

Introduction Pathological studies have shown that many atherosclerotic plaques destabilize without resulting in a clinical manifestation. Recent in vivo studies showed that healed plaques are more common in patients with chronic coronary syndrome (CCS) than in those with acute coronary syndrome (ACS), suggesting that they might be a marker of clinical stability. The aim of the present study was to evaluate the clinical impact of healed coronary plaques detected by optical coherence tomography (OCT) imaging. Methods A total of 208 patients with CCS or ACS who underwent OCT imaging of non-target/non-culprit vessels were enrolled. Only non-culprit segments were analyzed. Patients were divided into two groups according to the presence or absence of healed plaques detected by OCT. The incidence of major adverse cardiac events (MACE) at follow-up was assessed, defined as the composite of cardiac death, non-fatal myocardial infarction, and target vessel revascularization (TVR). Results Healed coronary plaques were observed in 39.7% of patients, and the prevalence was higher in those presenting with chronic coronary syndrome. Median follow-up time was 4 years, and was not different between the two groups. Patients with healed plaques had a significantly lower incidence of MACE at follow-up (13.6% vs 22%, p=0.019), mainly driven by a lower rate of non-fatal myocardial infarctions (4.9% vs 10.2%, p=0.05). The incidence of cardiac death and TVR was not significantly different between the two groups (1.2% vs. 3.1%, p=0.288; and 13.6% vs. 15.0%, p= 0.187, respectively). At multivariate Cox regression analysis, the presence of plaque disruption was an independent predictor of MACE (odds ratio [OR] 3.33, 95% confidence interval [CI] 1.39-7.98, p=0.007), while the presence of healed plaque was an independent protective factor (OR 0.44, 95% CI 0.22-0.89, p=0.022). Conclusions Healed coronary plaques detected by OCT imaging are associated with a favorable clinical outcome at long-term follow-up.

Background Current guidelines recommend that patients with heart failure and a reduced ejection fraction (HFrEF) should receive four foundational treatments, i.e. renin-angiotensin system inhibitor (RASi) or angiotensin-receptor neprilysin inhibitor (ARNi), β-blocker, mineralocorticoid receptor antagonist (MRA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i). There is emerging consensus that simultaneous initiation or rapid sequencing provide greater benefit, enhancing tolerability of these therapies and improving outcomes. However, implementation of a comprehensive approach is limited by common underuse and underdosing, and paucity of data exists on initiating the four pharmacological pillars of HFrEF during hospitalization or at discharge. Aim To investigate the feasibility of a comprehensive pharmacological approach in patients with HFrEF at discharge after an episode of heart failure (HF) hospitalization in a tertiary referral center. Methods In-patients with HFrEF and a first HF hospitalization (2019-2021) were categorized according to the number/type of treatments prescribed at discharge. Prevalence of contraindications and cautions for HFrEF treatments – as defined by current European Society of Cardiology (ESC) guidelines on HF – was as assessed. Logistic regression models were fitted to assess predictors of number of treatments prescribed and risk of re-hospitalization. Results Among 305 patients with HFrEF, 49.2% received at least two current recommended drugs. A β-blocker was prescribed in 93.4% of patients, and a RASi/ARNi in 68.2%. Based on current recommendations, 46.2% of patients could receive four foundational drugs. An MRA was prescribed in 32.5% of patients and 100% of patients did not show contraindications to MRA use. Renal dysfunction was present in 13.1% of patients, while hypotension in 11.8%. Bradycardia and renal dysfunction were associated with lower number of drugs prescribed [adjusted OR (95% CI) 0.18 (0.06-0.50), and 0.50 (0.39-0.64), respectively]. A higher number of drugs used was associated with no rehospitalization during the 30 days after discharge [OR (95% CI) 0.22 (0.10-0.49) per number of pillars increase]. Conclusions Based on the presence/absence of contraindications, a quadruple therapy could be implementable in a contemporary cohort of HFrEF in-patients at discharge. Renal dysfunction and bradycardia were the main prevalent conditions limiting the achievement of a more comprehensive therapeutic approach. Use of a higher number of drugs was associated with lower risk of re-hospitalization within 30 days after discharge.

Aims The guide extension catheter (GEC) is a helpful tool to increase catheter support when facing complex percutaneous coronary intervention (PCI) in unfavorable coronary anatomies. The aim of this study was to describe indication, efficacy, and safety of the GEC in a high-volume center. Methods and results From 2014 to 2021, we retrospectively identified and analyzed 351 interventional cases in which GEC was used to complete the procedure. The endpoints of the study were PCI success, procedural success and device failure. GEC use increased over the years and was more frequently used by radial approach (92.1%) in elective setting (90.6%) and using the 6F size (95.3%). The GEC was mostly implemented as bail-out strategy (75.9%) with the aim to improve back-up (89.6%), less frequently to optimize catheter alignment or obtain selective coronary cannulation (10.4%). Intracoronary advancement was performed using the guidewire in 1.3% of cases, after positioning of a second “buddy” wire in 23.2%, with support of a deflated balloon at the distal tip in 12.2%, or with anchoring technique in 63.3%. Mean coronary deep intubation depth was 38.8±23.9mm. Vessel and lesion characteristics are reported in Table I. Overall, PCI success rate was 92.5%, while procedural success (PCI success without in hospital adverse event) was 88.6%. GEC was successfully used in 92.7% of patients with no device-dependent severe adverse events; in particular, failures were related to inability to cross the target lesion in 4.5% or to device–related complication in 2.85% of cases. Conclusions This large real-world registry on GEC use in complex PCI confirms the GEC as a valid and safe tool to increase backup support and overcome the limits of conventional technique during complex PCI.

Background The clinical impact of valvular heart disease (VHD) in adult congenital heart disease (ACHD) patients is unascertained. Aim of our study was to assess the prevalence and clinical impact of severe VHD (S-VHD) in a real-world contemporary cohort of ACHD patients. Methods Patients followed-up at our ACHD Outpatient Clinic were enrolled. Clinical characteristics and echocardiographic data were prospectively entered into a digitalized medical records database. VHD at the first access was evaluated and graded according to VHD guidelines. Clinical data at follow-up were collected. Results A total of 390 patients were included and S-VHD was present in 101 (25.9%) patients. Over a median follow-up time of 26 months (IQR: 12-48), the primary composite endpoint occurred in 76 patients (19.5%). The cumulative primary endpoint-free survival was significantly lower in patients with S-VHD vs patients with non-severe VHD (Log rank p 45 mmHg. Conclusion In ACHD patients, the presence of S-VHD is independently associated with the occurrence of cardiovascular mortality and hospitalization. The prognostic value of S-VHD is incremental above other established prognostic markers.

Background Left main coronary artery disease (LMCAD) heavily affects prognosis of patients with suspected CAD. Thus, its identification/exclusion is an important step in the assessment of these patients. Although being the gold standard to identify LMCAD, invasive coronary angiography (ICA) is burdened by some risks, while coronary computed tomography angiography (CCTA) has still limited availability, quite high costs and associated radiologic risks. In the past decades, several studies demonstrated the utility of ECG exercise stress test (EST) for the identification of LM disease in patients with suspected CAD. However, the pre-test probability of CAD of subjects undergoing EST has significantly changed in the last decades. Accordingly, in this study we aimed to assess the predictive value of EST for the presence/absence of LMCAD in a contemporary population of patients with suspected CAD. Methods We retrospectively enrolled 495 consecutive patients, referred to our Center between years 2018 and 2021 because of suspected CAD, who underwent both an EST (standard treadmill Bruce protocol) and ICA (within 12 months of the EST). Patients with a history of coronary artery bypass surgery were excluded. Results Overall, 24 patients (4.8%) were found to have LMCAD at ICA. Among clinical variables, only male gender (p=0.025) and smoking (p=0.003) were associated with LMCAD. A number of ECG leads with EST-induced ST-segment depression (STD) ≥5 and a maximal STD ≥2 mm were more frequently found in patients with, compared to those without LMCAD (29.2 vs 9.8%, p=0.003; and 58.3 vs 24.8%, p Conclusions Our data indicate that EST continues to be a valuable tool for predicting the presence/absence of LMCAD in contemporary populations of patients with suspected coronary artery disease.

Takotsubo syndrome (TTS) is a rare cardiac disease, characterized by transient regional wall motion abnormalities without evidence of obstructive coronary artery stenoses, mainly triggered by emotion or physical stressors. Reverse Takotsubo syndrome (rTTS), an atypical variant with basal segments involvement, is frequently associated with neurological disorders, including patients with amyotrophic lateral sclerosis (ALS). We reported the case of a 54 years old woman who experienced two consecutive episodes of TTS with different wall motion patterns, complicated by a recurrent episode and arrhythmic events. A Caucasian woman, affected by ALS, was hospitalized in our department due to anemia and recurrent episodes of hematochezia. Following a week of relative clinical stability, the patient experienced acute deterioration with generalized malaise and worsening dyspnea. CT scan excluded pulmonary causes, whereas EKG (ST segment depression in the lower and lateral leads), blood test (increase in high-sensitive cardiac troponins) and TTE (severe impairment of LVEF, with akinesia of basal segments) revealed a cardiac etiology. Coronary angiography and left ventriculography were performed, documenting a wall motion pattern consistent with rTTS. After an initial management in intensive care unit, clinical stability was obtained with a complete recovery of left ventricular systolic function. The patient was discharged but one month later, due to bacterial pneumonia, she was readmitted in our ward and antibiotic therapy was started. Two days later an acute deterioration of clinical status occurred, characterized by dyspnea, altered state of consciousness and marked hypotension. TTE revealed a severe left ventricular systolic dysfunction with apical akinesia and preserved contractility of basal segments, so a diagnosis of typical TTS was made. Three weeks later the clinical scenario became more complicated due to advanced atrioventricular block, with phases of atrioventricular dissociation and ventricular escape-rhythm. Therefore, in light of the increased risk of infectious complications, she underwent implantation of a leadless pacemaker (PMK). This clinical case represents the first report of recurrent episodes of TTS, one of which as rTTS, in a patient affected by ALS. It is worth noting that the first episode of TTS had atypical clinical presentation (dyspnea without chest pain), the EKG showed diffuse ST-segment depression (totally different from classical TTS typical electrocardiographic alterations), and TTE confirmed a different phenotype of segment involvement (unsurprisingly InterTAK Diagnostic Score was low). TTS recurrence is an extremely rare event, even if in this case there were two well defined triggers such as anemia and pneumonia. On the other hand it is reasonable to think that non-use of BBs after the first episode may have contributed to the occurrence of the next event, affecting different segments compared to the previous episode. Furthermore, advanced atrioventricular (AV) block represents a rare complication of TTS, most probably due to catecholamine stress or increased vagal tone, often requiring PMK implantation. In conclusion TTS represents an important frequent cardiac complication in patients affected by ALS, often still underdiagnosed. Therefore clinicians must keep their guard up with TTS, especially in the cases with atypical clinical presentation.

Background Coronary vasomotor abnormalities are important causes of myocardial ischemia in patients with non-obstructive coronary artery disease (NOCAD). However, the role of air pollution in determining coronary vasomotor disorders has never been investigated. Objectives We aimed to evaluate the association between long-term exposure to particulate matter 2.5 (PM2.5) and 10 (PM10), and coronary vasomotor disorders in NOCAD patients. Methods Patients with myocardial ischemia and NOCAD undergoing coronary angiography and intracoronary provocation test with acetylcholine (ACh) were prospectively studied. Both patients with chronic myocardial ischemia (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA) were enrolled. Based on each case's home address, exposure to PM2.5 and PM10 was assessed. Results We included 287 patients (median age 62.0 years [52.0-70.0], 149 [51.9%] males): 161 (56.1%) INOCA and 126 (43.9%) MINOCA. One hundred seventy-six patients (61.3%) had positive provocation test. Exposure to PM2.5 and PM10 was higher in patients with a positive provocation test (p Conclusions Higher exposure to PM2.5 and PM10 in patients with myocardial ischemia and NOCAD is associated with coronary vasomotor abnormalities. In particular, PM2.5 is an independent risk factor for the occurrence of epicardial spasm and MINOCA as clinical presentation.

Background Although the detection of a rise and/or fall pattern of cardiac troponin (cTn) serum levels in presence of a clinical context of acute myocardial ischemia, represents the main criterion for the diagnosis of acute myocardial infarction (AMI), troponins may increase in various conditions of myocardial injury different from ischemic myocardial necrosis or simply following myocardial ischemia, in the absence of cell necrosis. Some studies found that troponins also increase after physical exertion and other types of stressful stimuli in the absence of obstructive CAD and myocardial ischemia. No previous study, however, investigated the relation between cTn serum levels and the extent of myocardial ischemia in patients with a suspect of CCS. Methods We prospectively enrolled consecutive patients undergoing an elective stress myocardial perfusion scintigraphy (MPS) because of a clinical suspicion of obstructive coronary artery disease (CAD). Patients were divided into 3 groups based on the evidence and degree of stress-induced MI at MPS: 1) group 1, no MI (≤4%); 2) group 2, mild MI (5-10%); 3) group 3, moderate-to-severe MI (≥10%). High sensitivity (hs)-cTnI was measured immediately before (T0) and 1 hour (T1) and 4 hours (T2) after the stress test. A successive evaluation of patients was performed at 24 months. Results One-hundred consecutive patients (64 males; age 65.5±9.5 years) were enrolled in the study. Serum hs-cTnI concentrations significantly increased after MPS, compared to baseline, in the whole population, from (median, interquartile range) 3.9 (2.5-6.1) ng/L at T0, to 4.2 (2.8-7.3) ng/L at T1 (p Conclusions In patients with suspected CAD, stress MPS induces an increase of cTnI that is independent of the induction and the extent of myocardial ischemia and is mainly related to myocardial work, as indicated by HR achieved during the test.

Background Takotsubo syndrome (TTS) is associated with a non-negligible risk of in-hospital complications. Elevated left ventricular filling pressures (LVFP) showed to predict adverse outcomes in this population. Recently, LA reservoir and LA pump strain, demonstrated a close correlation with increased LVFP in unselected patients. The aim of our study is to assess the ability of LA strain analysis to improve non-invasive estimation of LVFP and to predict IH complications in TTS patients. Methods We prospectively enrolled patients with confirmed TTS diagnosis. LVEDP was assessed invasively at the time of catheterization. Transthoracic echocardiography was performed within 48 hours from hospital admission. In-hospital complications were collected, including occurrence of acute heart failure, death from any cause and life-threatening arrhythmias. Results A total of 62 patients were analysed (72.2±10.1 years, female 80%). In-hospital complications occurred in 25 (40.3%). Patients who experienced IH complications had higher LVEDP and lower LVEF, LA reservoir strain and LA pump strain values compared to patients without IH complications (all p24.5 mmHg in comparison with E/e’, LAVi and tricuspid regurgitation (TR) peak velocity. Moreover, the incorporation of LA strain values in a multivariable model including E/e’ ratio, LAVi and TR peak velocity to predict a LVEDP>24.5 mmHg led to a significant incremental predictive value (p=0.002). Conclusion In patients with TTS, lower LA reservoir and pump strain values correlate with increased LVEDP and improve non-invasive estimation of LVFP. LA strain analysis may be an easy tool to individuate subjects at higher risk of in-hospital complications.

Background Myocardial bridging (MB) is a congenital epicardial coronary abnormality, in which a segment of the artery runs through the myocardium, determining dynamic stenosis during systole. Whether MB can be responsible by itself for myocardial ischemia remains unclear. Thus, we aimed to evaluate whether the dynamic stenosis related to MB can cause signs and symptoms of myocardial ischemia. Methods We enrolled 41 consecutive patients who underwent coronary angiography because of chest pain suspected for ischemic heart disease and were found to have MB in the absence of any significant flow-limiting coronary stenosis and any other cardiac disease. A group of 14 patients who also underwent coronary angiography because of chest pain suspected for ischemic heart disease, but found to be free of any coronary or cardiac abnormality (including MB) and also showed negative results at exercise stress test (EST) served as controls. All enrolled patients underwent a maximal treadmill EST according to standard Bruce protocol. A complete echocardiographic examination was performed at rest and at peak exercise. Results Baseline EST parameters were comparable between groups, whereas peak diastolic blood pressure (pDBP) was slightly higher in the MB group (p=0.044). No clinically significant differences were found in baseline echocardiographic parameters, although the E wave deceleration time (DcT) was longer (p=0.038) and global longitudinal strain (GLS) was higher (p=0.05) in the MB group. During exercise, left ventricular ejection fraction (LVEF) improved significantly in both groups (p Moreover, among MB patients, no differences were found in stress echocardiographic results between those with positive vs. those with negative EST. Conclusions We failed to demonstrate any significant ischemic impairment of LV systolic and diastolic function at maximal EST in patients with MB. Moreover, we also failed to demonstrate any LV dysfunction in MB patients that developed ECG signs of myocardial ischemia during EST, as compared to those without evidence of myocardial ischemia. Thus, our data question about the ability of MB itself to trigger significant myocardial ischemia in clinical practice.

Coronary microvascular dysfunction (CMD) may cause symptoms of myocardial ischemia (microvascular angina [MVA]), but recent studies suggested that it might also contribute to the syndrome of heart failure with preserved ejection fraction (HFpEF). In this study we assessed the relation of CMD with findings of HFpEF in MVA patients.We enrolled 36 consecutive patients with MVA, in whom we assessed: 1) coronary blood flow (CBF) response to adenosine and cold pressor test (CPT) by color-Doppler echocardiography of the left anterior descending coronary artery; 2) complete echocardiographic examination; 3) N-terminal-pro-B-natriuretic peptide (NT-proBNP); 4) grade of dyspnea by the modified Medical Research Scale.Among patients, 15 had definite HFpEF findings (group 1), 12 had equivocal HFpEF findings (group 2) and 9 had no evidence of HFpEF findings (group 3). Group 1 patients were older, had more cardiovascular risk factors and higher NT-proBNP levels (P=0.018), and showed a higher prevalence of diastolic dysfunction. Left ventricle dimensions and systolic function, however, did not differ among groups. Dyspnea was also not significantly different among groups (P=0.19). CBF to adenosine was 1.85±0.47, 1.78±0.40 1.49±0.32 in group 1, 2 and 3, respectively (P=0.13). Similarly, CBF response to CPT was 1.57±0.4, 1.49±0.2 and 1.45±0.3 in the 3 groups, respectively (P=0.74). Both CBF response to adenosine and CPT showed no relation with the severity of dyspnea symptoms.Our data suggest that in patients with MVA there is no relation between the grade of impairment of coronary microvascular dilatation and findings of HFpEF.

Recent trials demonstrated the clinical efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure (HF), regardless of the presence or absence of type 2 diabetes. These data may allow the use of this innovative drug class in clinical routine for treating these patients.We aimed at further clarifying the role of SGLT2i in patients with diagnosis of HF, capitalizing on pooled sample size and heightened power for clinically relevant safety and efficacy outcomes.We conducted a systematic search of PubMed, reference lists of relevant articles, and Medline database from inception until March 1, 2021.This meta-analysis was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched for randomized trials that evaluated the cardiovascular effects of SGLT2i in patients with HF. Three investigators independently assessed study eligibility, extracted the data, and assessed risk of bias. Hazard ratios and 95% confidence intervals (CIs) were pooled and meta-analyzed using a random-effect model. Numbers needed to treat (NNT) with the relative 95% CIs were also calculated. The primary outcome was a composite of HF hospitalization or an urgent visit for worsening HF and cardiovascular death.Three trials were included in the study. Overall, treatment with SGLT2i was associated with a lower risk of the primary composite outcome [hazard ratios 0.73, 95% CI (0.67-0.80), NNT = 11.3]. Similarly, there was a significantly reduced risk of cardiovascular death, all-cause death, HF hospitalization and need for urgent treatment for HF, and HF hospitalization.Therefore, the available evidence supports the routine use of these drugs as standard-of-care, also given the highly favorable NNTs.

Background: South Asians, and Indians in particular, are known to have a higher incidence of premature atherosclerosis and acute coronary syndromes (ACS) with worse clinical outcomes, compared to populations with different ethnic backgrounds. However, the underlying pathobiology accounting for these differences has not been fully elucidated. Methods: ACS patients who had culprit lesion optical coherence tomography (OCT) imaging were enrolled. Culprit plaque characteristics were evaluated using OCT. Results: Among 1315 patients, 100 were South Asian, 1009 were East Asian, and 206 were White. South Asian patients were younger (South Asians vs. East Asians vs. Whites: 51.6 ± 13.4 vs. 65.4 ± 11.9 vs. 62.7 ± 11.7; p < 0.001) and more frequently presented with ST-segment elevation myocardial infarction (STEMI) (77.0% vs. 56.4% vs. 35.4%; p < 0.001). On OCT analysis after propensity group matching, plaque erosion was more frequent (57.0% vs. 38.0% vs. 50.0%; p = 0.003), the lipid index was significantly greater (2281.6 [1570.8–3160.6] vs. 1624.3 [940.9–2352.4] vs. 1303.8 [1090.0–1757.7]; p < 0.001), and the prevalence of layered plaque was significantly higher in the South Asian group than in the other two groups (52.0% vs. 30.0% vs. 34.0%; p = 0.003). Conclusions: Compared to East Asians and Whites, South Asians with ACS were younger and more frequently presented with STEMI. Plaque erosion was the predominant pathology for ACS in South Asians and their culprit lesions had more features of plaque vulnerability. Clinical Trial Registration: http://www.clinicaltrials.gov, NCT03479723