Search

Abstract Aims Several mechanisms have been identified in the aetiopathogenesis of heart failure with preserved ejection fraction (HFpEF). Among these, coronary microvascular dysfunction (CMD) may play a key pathophysiological role. We performed a systematic review and meta‐analysis to investigate the prevalence, echocardiographic correlates, and prognostic implications of CMD in patients with HFpEF. Methods and results A systematic search for articles up to 1 May 2023 was performed. The primary aim was to assess the prevalence of CMD. Secondary aims were to compare key echocardiographic parameters (E/e′ ratio, left atrial volume index [LAVi], and left ventricular mass index [LVMi]), clinical outcomes [death and hospitalization for heart failure (HF)], and prevalence of atrial fibrillation (AF) between patients with and without CMD. Meta‐regressions according to baseline patient characteristics and study features were performed to explore potential heterogeneity sources. We identified 14 observational studies, enrolling 1138 patients with HFpEF. The overall prevalence of CMD was 58%. Compared with patients without CMD, patients with HFpEF and CMD had larger LAVi [mean difference (MD) 3.85 confidence interval (CI) 1.19–6.5, P

Abstract Aims Chimeric Antigen Receptor-T (CAR-T) cell infusion is a rapidly evolving antitumor therapy; however, cardiovascular (CV) complications, likely associated with cytokine release syndrome (CRS) and systemic inflammation, have been reported to occur. The CARdio-Tox study aimed at elucidating incidence and determinants of cardiotoxicity related to CAR-T cell therapy. Methods Patients with blood malignancies candidate to CAR-T cells were prospectively evaluated by echocardiography at baseline and 7 and 30 days after infusion. The study endpoints were i) incidence of cancer therapy-related cardiac dysfunction (CTRCD), CTRCD were also balanced for any grade CRS, but CTRCD occurred of Cardiology Guidelines on Cardio-Oncology (decrements of left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) and/or elevations of cardiac biomarkers (high sensitivity troponin I, natriuretic peptides) and ii), correlations of echocardiographic metrics with inflammatory biomarkers. Results Incidence of CTRCD was high at 7 days (59,3%), particularly in subjects with CRS. The integrated definition of CTRCD allowed the identification of the majority of cases (50%). Moreover, early LVEF and GLS decrements were inversely correlated with fibrinogen and interleukin-2 receptor levels (p always ≤ 0.01). Conclusions There is a high incidence of early CTRCD in patients treated with CAR-T cells, and a link between CTRCD and inflammation can be demonstrated. Dedicated patient monitoring protocols are advised. Graphical Abstract

Abstract Aims Cardiac contractility modulation (CCM) is a device therapy for heart failure, based on the delivery of high‐voltage biphasic impulses to the right ventricular septum during the myocardial absolute refractory period. This study evaluated the cost‐effectiveness of CCM therapy plus optimal medical therapy (OMT) vs. OMT alone in patients with heart failure with reduced ejection fraction. Methods and results A Markov model with a lifespan time horizon was developed to assess the cost–utility using the FIX trials as main data sources. A deterministic sensitivity analysis and a probabilistic sensitivity analysis were run to analyse the decision uncertainty in the model through cost‐effectiveness acceptability curve (CEAC) and cost‐effectiveness acceptability frontier (CEAF). Value of information analysis was also conducted computing the expected value of perfect information (EVPI) and the expected value of partial perfect information. The base case results showed that the CCM plus OMT option was highly cost‐effective compared with OMT alone with an incremental cost–utility ratio of €7034/quality‐adjusted life year (QALY). The CEAC and CEAF illustrated that for all willingness to pay levels above €5600/QALY, tested up to €50 000/QALY, CCM plus OMT alternative had the highest probability of being cost‐effective. The EVPI per patient was estimated to be €124 412 on a willingness to pay threshold of €30 000/QALY. Conclusions For patients with heart failure with reduced ejection fraction, CCM therapy could be cost‐effective when taking a lifetime horizon. Further long‐term, post‐approval clinical studies are needed to verify these results in a real‐world context, particularly concerning the effect of CCM therapy on mortality.

Abstract Objective We recently demonstrated that treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) leads to an increase in myocardial flow reserve in patients with type 2 diabetes (T2D) with stable coronary artery disease (CAD). The mechanism by which this occurs is, however, unclear. One of the risk factors for cardiovascular disease is inflammation of epicardial adipose tissue (EAT). Since the latter is often increased in type 2 diabetes patients, it could play a role in coronary microvascular dysfunction. It is also well known that SGLT-2i modify adipose tissue metabolism. We aimed to investigate the effects of the SGLT-2i dapagliflozin on metabolism and visceral and subcutaneous adipose tissue thickness in T2D patients with stable coronary artery disease and to verify whether these changes could explain observed changes in myocardial flow. Methods We performed a single-center, prospective, randomized, double-blind, controlled clinical trial with 14 T2D patients randomized 1:1 to SGLT-2i dapagliflozin (10 mg daily) or placebo. The thickness of visceral (epicardial, mediastinal, perirenal) and subcutaneous adipose tissue and glucose uptake were assessed at baseline and 4 weeks after treatment initiation by 2-deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography/Computed Tomography during hyperinsulinemic euglycemic clamp. Results The two groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, BMI, renal and heart function). Dapagliflozin treatment significantly reduced EAT thickness by 19% (p = 0.03). There was a significant 21.6% reduction in EAT glucose uptake during euglycemic hyperinsulinemic clamp in the dapagliflozin group compared with the placebo group (p = 0.014). There were no significant effects on adipose tissue thickness/metabolism in the other depots explored. Conclusions SGLT-2 inhibition selectively reduces EAT thickness and EAT glucose uptake in T2D patients, suggesting a reduction of EAT inflammation. This could explain the observed increase in myocardial flow reserve, providing new insights into SGLT-2i cardiovascular benefits.

Abstract Background Renal ischemia/reperfusion injury is an unavoidable event in transplantation in which free radical-mediated injury determines release of pro-inflammatory cytokines and activation of innate immunity. In addition to their cholesterol-lowering action, statins have shown dose-dependent pleiotropic effects on inflammatory pathways and oxidative stress. We investigated the effects of high-dose atorvastatin (atorvastatin 40 mg/kg) in preventing ischemia/reperfusion injury in an animal model of kidney transplant. Methods Forty female rats underwent left nephrectomy and orthotopic autotransplantation. Animals were divided in four groups: A = Transplant only; B = high-dose atorvastatin + Transplant; C = right nephrectomy + Transplant; D = high-dose atorvastatin + right nephrectomy + Transplant. Bilateral nephrectomy was performed 24 h post-transplant. Oxidative stress was assessed measuring malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activity on renal tissue; ischemia/reperfusion injury was also evaluated by histology. Donor pre-treatment with high-dose atorvastatin improved oxidative stress. Results MDA levels were lower in group B versus A (p = 0.002) and D (p = 0.004). High-dose atorvastatin pre-treated rats displayed higher GPx activity in group B versus A (p = 0.009) and D (p = 0.005). SOD scavenger activity was also higher in group B versus A (p

Abstract Gut microbiota is an emerging editable cardiovascular risk factor. We aim to investigate gut and coronary plaque microbiota, using fecal samples and angioplasty balloons from patients with acute coronary syndrome (ACS), chronic coronary syndrome (CCS) and control subjects. We examined bacterial communities in gut and coronary plaques by 16S rRNA sequencing and we performed droplet digital PCR analysis to investigate the gut relative abundance of the bacterial genes CutC/CntA involved in trimethylamine N-oxide synthesis. Linear discriminant analysis effect size (LEfSe) at the genus and species levels displayed gut enrichment in Streptococcus, Granulicatella and P. distasonis in ACS compared with CCS and controls; Roseburia, C. aerofaciens and F. prausnitzii were more abundant in controls than in patients. Principal component analysis (PCA) of 41 differentially abundant gut taxa showed a clustering of the three groups. In coronary plaque, LEfSe at the genus level revealed an enrichment of Staphylococcus and Streptococcus in ACS, and Paracoccus in CCS, whereas PCA of 15 differentially abundant plaque taxa exhibited clustering of ACS and CCS patients. CutC and CntA genes were more abundant in ACS and CCS than in controls while no significant difference emerged between ACS and CCS. Our results indicate that ACS and CCS exhibit a different gut and plaque microbial signature, suggesting a possible role of these microbiotas in coronary plaque instability.

Background: Age-related remodelling has the potential to affect the microvascular response to hyperemic stimuli. However, its precise effects on the vasodilatory response to adenosine and contrast medium, as well as its influence on fractional flow reserve (FFR) and contrast fractional flow reserve (cFFR), have not been previously investigated. We investigate the impact of age on these indices. Methods: We extrapolated data from the post-revascularization optimization and physiological evaluation of intermediate lesions using fractional flow reserve (PROPHET-FFR) and The Multi-center Evaluation of the Accuracy of the Contrast MEdium INduced Pd/Pa RaTiO in Predicting (MEMENTO) studies. Only lesions with a relevant vasodilatory response to adenosine and contrast medium were considered of interest. A total of 2080 patients, accounting for 2294 pressure recordings were available for analysis. The cohort was stratified into three age terciles. Age-dependent correlations with FFR, cFFR, distal pressure/aortic pressure (Pd/Pa) and instantaneous wave-free ratio (iFR) were calculated. The vasodilatory response was calculated in 1619 lesions (with both FFR and cFFR) as the difference between resting and hyperaemic pressure ratios and correlated with aging. The prevalence of FFR-cFFR discordance was assessed. Results: Age correlated positively to FFR (r = 0.062, p = 0.006), but not with cFFR (r = 0.024, p = 0.298), Pd/Pa (r = –0.015, p = 0.481) and iFR (r = –0.026, p = 0.648). The hyperemic response to adenosine (r = –0.102, p ≤ 0.0001) and to contrast medium (r = –0.076, p = 0.0023) showed a negative correlation with age. When adjusted for potential confounders, adenosine induced hyperaemia was negatively associated with age (p = 0.04 vs p = 0.08 for cFFR). Discordance decreased across age terciles (14.64% vs 12.72% vs 10.12%, p = 0.032). Conclusions: As compared to adenosine, contrast induced hyperaemia appeared to be less affected by age. cFFR may be considered a more stable and reproducible tool to assess epicardial stenosis in elderly patients. Clinical Trial Registration: PROPHET-FFR STUDY, Clinicaltrials.gov (NCT05056662).

Therapeutic Area: ASCVD/CVD in Women Background: Women with obstructive coronary artery disease (CAD) have a relatively lower quality of life (QoL) compared to men but our understanding of sex differences in QoL in ischemia with no obstructive coronary artery disease (INOCA) is limited. Methods: We conducted a survey of patient members of INOCA International with an assessment of self-reported health measures. Functional capacity was retrospectively estimated using the Duke Activity Status Index (DASI) assessing levels of activities performed before and after INOCA symptom onset. Results: Of the 1579 patient members of INOCA International, the overall survey completion rate was 21%. Women represented 91% of the respondents. Estimated functional capacity, expressed as metabolic equivalents (METs), was higher before compared to after INOCA diagnosis for comparably for both women (8.6±1.8 METs vs. 5.6±1.8 METs respectively, p

Abstract Background Several cohort studies aimed at demonstrating an increased risk of cancer incidence and mortality in patients with a pre-existing diagnosis of heart failure (HF); however, conflicting results have been reported that call for systematic review and meta-analysis. Methods We conducted a systematic search of multiple databases from their inception through July 2022 and retrieved only papers reporting hazard ratios (HR). Random and fixed-effects models were fit for the study duration. Results The analysis included nine cohort studies for a total of 515′041 HF cases and 1′365’452 controls without HF. Although high heterogeneity among studies was observed, the HR for incident cancer in HF patients was statistically significant (1.45, 95% CI 1.31–1.61, p

Abstract Background Patients with type 2 diabetes mellitus (T2DM) are considered as a homogeneous cohort of patients. However, the specific role of diabetic microvascular complications (DMC), in determining the features of coronary plaques is poorly known. We investigated whether the presence of DMC may identify a different phenotype of patients associated to specific clinical, angiographic, optical coherence tomography (OCT) features and different prognosis. Methods We prospectively enrolled consecutive T2DM patients with obstructive coronary artery disease (CAD) at their first coronary event. Patients were stratified according to the presence or absence of DMC, including diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. OCT assessment of the culprit vessel was performed in a subgroup of patients. The incidence of major adverse cardiac events (MACEs) was assessed at follow-up. Results We enrolled 320 T2DM patients (mean age 70.3 ± 8.8 years; 234 [73.1%] men, 40% acute coronary syndrome, 60% chronic coronary syndrome). Patients with DMC (172 [53.75%]) presented a different clinical and biochemical profile and, of importance, a higher prevalence of multivessel CAD (109 [63.4%] vs. 68 [45.9%], p = 0.002). At OCT analysis, DMC was associated to a higher prevalence of large calcifications and healed plaques and to a lower prevalence of lipid plaques. Finally, MACEs rate was significantly higher (25 [14.5%] vs. 12 [8.1%], p = 0.007) in DMC patients, mainly driven by a higher rate of planned revascularizations, and DMC predicted the occurrence of MACEs (mean follow-up 33.4 ± 15.6 months). Conclusions The presence of DMC identifies a distinct diabetic population with more severe CAD but with a more stable pattern of coronary atherosclerosis.

Abstract Objective Cardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and 6 months) but no HF. Methods This was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by 13N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT 03313752). Results 16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 μmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 μmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; pint = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; pint = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054). Conclusions SGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction. Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752

Background Guidelines recommend using multiple drugs in patients with heart failure (HF) with reduced ejection fraction, but there is a paucity of real‐world data on the simultaneous initiation of the 4 pharmacological pillars at discharge after a decompensation event. Methods and Results A retrospective data mart, including patients diagnosed with HF, was implemented. Consecutively admitted patients with HF with reduced ejection fraction were selected through an automated approach and categorized according to the number/type of treatments prescribed at discharge. The prevalence of contraindications and cautions for HF with reduced ejection fraction treatments was systematically assessed. Logistic regression models were fitted to assess predictors of the number of treatments (≥2 versus

BackgroundHeart failure (HF) is a multifaceted clinical syndrome characterized by different etiologies, risk factors, comorbidities, and a heterogeneous clinical course. The current model, based on data from clinical trials, is limited by the biases related to a highly-selected sample in a protected environment, constraining the applicability of evidence in the real-world scenario. If properly leveraged, the enormous amount of data from real-world may have a groundbreaking impact on clinical care pathways. We present, here, the development of an HF DataMart framework for the management of clinical and research processes.MethodsWithin our institution, Fondazione Policlinico Universitario A. Gemelli in Rome (Italy), a digital platform dedicated to HF patients has been envisioned (GENERATOR HF DataMart), based on two building blocks: 1. All retrospective information has been integrated into a multimodal, longitudinal data repository, providing in one single place the description of individual patients with drill-down functionalities in multiple dimensions. This functionality might allow investigators to dynamically filter subsets of patient populations characterized by demographic characteristics, biomarkers, comorbidities, and clinical events (e.g., re-hospitalization), enabling agile analyses of the outcomes by subsets of patients. 2. With respect to expected long-term health status and response to treatments, the use of the disease trajectory toolset and predictive models for the evolution of HF has been implemented. The methodological scaffolding has been constructed in respect of a set of the preferred standards recommended by the CODE-EHR framework.ResultsSeveral examples of GENERATOR HF DataMart utilization are presented as follows: to select a specific retrospective cohort of HF patients within a particular period, along with their clinical and laboratory data, to explore multiple associations between clinical and laboratory data, as well as to identify a potential cohort for enrollment in future studies; to create a multi-parametric predictive models of early re-hospitalization after discharge; to cluster patients according to their ejection fraction (EF) variation, investigating its potential impact on hospital admissions.ConclusionThe GENERATOR HF DataMart has been developed to exploit a large amount of data from patients with HF from our institution and generate evidence from real-world data. The two components of the HF platform might provide the infrastructural basis for a combined patient support program dedicated to continuous monitoring and remote care, assisting patients, caregivers, and healthcare professionals.

IntroductionMonomorphic ventricular tachycardia (VT) is a life-threatening condition often observed in patients with structural heart disease. Ventricular tachycardia ablation through radiation therapy (VT-ART) for sustained monomorphic ventricular tachycardia seems promising, effective, and safe. VT-ART delivers focused, high-dose radiation, usually in a single fraction of 25 Gy, allowing ablation of VT by inducing myocardial scars. The procedure is fully non-invasive; therefore, it can be easily performed in patients with contraindications to invasive ablation procedures. Definitive data are lacking, and no direct comparison with standard procedures is available.DiscussionThe aim of this multicenter observational study is to evaluate the efficacy and safety of VT-ART, comparing the clinical outcome of patients undergone to VT-ART to patients not having received such a procedure. The two groups will not be collected by direct, prospective accrual to avoid randomization among the innovative and traditional arm: A retrospective selection through matched pair analysis will collect patients presenting features similar to the ones undergone VT-ART within the consortium (in each center independently). Our trial will enroll patients with optimized medical therapy in whom endocardial and/or epicardial radiofrequency ablation (RFA), the gold standard for VT ablation, is either unfeasible or fails to control VT recurrence. Our primary outcome is investigating the difference in overall cardiovascular survival among the group undergoing VT-ART and the one not exposed to the innovative procedure. The secondary outcome is evaluating the difference in ventricular event-free survival after the last procedure (i.e., last RFA vs. VT-ART) between the two groups. An additional secondary aim is to evaluate the reduction in the number of VT episodes comparing the 3 months before the procedure to the ones recorded at 6 months (from the 4th to 6th month) following VT-ART and RFA, respectively. Other secondary objectives include identifying the benefits of VT-ART on cardiac function, as evaluated through an electrocardiogram, echocardiographic, biochemical variables, and on patient quality of life. We calculated the sample size (in a 2:1 ratio) upon enrolling 149 patients: 100 in the non-exposed control group and 49 in the VT-ART group. Progressively, on a multicentric basis supervised by the promoting center in the VT-ART consortium, for each VT-ART patient enrollment, a matched pair patient profile according to the predefined features will be shared with the consortium to enroll a patient that has not undergone VT-ART.ConclusionOur trial will provide insight into the efficacy and safety of VT-ART through a matched pair analysis, via an observational, multicentric study of two groups of patients with or without VT-ART in the multicentric consortium (with subgroup stratification into dynamic cohorts).

Chimeric antigen receptor-T (CAR-T) cells therapies represent an innovative immunological treatment for patients suffering from advanced and refractory onco-hematological malignancies. The infusion of engineered T-cells, exposing chimeric receptors on the cell surface, leads to an immune response against the tumor cells. However, data from clinical trials and observational studies showed the occurrence of a constellation of adverse events related to CAR-T cells infusion, ranging from mild effects to life-threatening organ-specific complications. In particular, CAR-T cell-related cardiovascular toxicities represent an emerging group of adverse events observed in these patients, correlated with increased morbidity and mortality. Mechanisms involved are still under investigation, although the aberrant inflammatory activation observed in cytokine release syndrome (CRS) seems to play a pivotal role. The most frequently reported cardiac events, observed both in adults and in the pediatric population, are represented by hypotension, arrhythmias and left ventricular systolic dysfunction, sometimes associated with overt heart failure. Therefore, there is an increasing need to understand the pathophysiological basis of cardiotoxicity and risk factors related to its development, in order to identify most vulnerable patients requiring a close cardiological monitoring and long-term follow-up. This review aims at highlighting CAR-T cell-related cardiovascular complications and clarifying the pathogenetic mechanisms coming at play. Moreover, we will shed light on surveillance strategies and cardiotoxicity management protocols, as well as on future research perspectives in this expanding field.

Background and aimsEdoxaban proved to be safe and effective also in fragile patients, but its administration through percutaneous endoscopic gastrostomy (PEG) has not been previously investigated. The purpose of this study was to evaluate the feasibility and the preliminary safety and efficacy profiles of edoxaban administered via PEG in patients with an indication for long-term oral anticoagulation.MethodsORIGAMI was a prospective, single-arm, observational study (NCT04271293). Patients with PEG and an indication for long-term anticoagulation were prospectively enrolled. Crushed edoxaban at approved doses was administered via PEG. The primary endpoint was the composite of cardio-embolic events consisting of ischemic stroke, systemic embolism, or symptomatic deep venous thrombosis/pulmonary embolism (DVT/PE). Secondary endpoints were the number of bleeding events and edoxaban plasma concentrations at steady state. We here report the 12-month results.ResultsA total of 12 patients were enrolled. The main indication for PEG implantation was amyotrophic lateral sclerosis (10/12). The primary endpoint of cardio-embolic events did not occur in any patients at 12 months. All patients were in the therapeutic range of steady-state edoxaban plasma levels. Three minor bleedings were observed, while no major bleedings occurred during the observational period. A total of five patients died. All deaths were from non-cardiovascular causes and were consistent with the natural history of the pre-existing severe disease.ConclusionOur study suggests that edoxaban administration via PEG is feasible and appears safe and effective in fragile, comorbid patients, resulting in therapeutic plasma concentrations of edoxaban.Clinical trial registration[ClinicalTrials.gov], identifier [NCT04271293].

BackgroundIn ST-segment elevation myocardial infarction (STEMI), predictors of subclinical dysfunction of remote myocardium are unknown. We prospectively aimed at identifying clinical and biochemical correlates of remote subclinical dysfunction and its impact on left ventricular ejection fraction (LVEF).MethodsOne-hundred thirty-three patients (63.9 ± 12.1 years, 68% male) with first successfully treated (54% anterior, 46% non-anterior, p = 0.19) STEMI underwent echocardiography at 5 ± 2 days after onset and at 8 ± 2-month follow-up, and were compared to 13 age and sex-matched (63.3 ± 11.4) healthy controls. All 16 left ventricular (LV) segments were grouped into ischemic, border, and remote myocardium: mean value of longitudinal strain (LS) within grouped segments were expressed as iLS, bLS, rLS, respectively. LV end-diastolic (EDV), end-systolic (ESV) volumes indexed for body surface area (EDVi, ESVi, respectively), LVEF and global LS (GLS) were determined. Creatinine, glomerular filtration rate, admission level of NT-pro-brain-natriuretic peptide (NT-proBNP) and troponin peaks were considered for the analysis.ResultsAt baseline, rLS (15.5 ± 4.4) was better than iLS (12.9 ± 4.8, p < 0.001), but lower than that in controls (19.1 ± 2.7, p < 0.001) and similar to bLS (15 ± 5.4, p = ns), and did not differ between patients with single or multivessel coronary artery disease (CAD). At multivariate regression analysis, only admission NT-proBNP levels but not peak Tn levels independently predicted rLS (β = −0.58, p = 0.001), as well as iLS (β = −0.52, p = 0.001). Both at baseline and at follow-up, rLS correlated to LVEF similarly to iLS and bLS (p < 0.001 for all). Median value of rLS at baseline was 15%: compared to patients with rLS ≥ 15% at baseline, patients with rLS < 15% showed lower LVEF (52.3 ± 9.4 vs. 58.6 ± 7.6, p < 0.001) and GLS (16.3 ± 3.9 vs. 19.9 ± 3.2), and higher EDVi (62.3 ± 19.9 vs. 54 ± 12, p = 0.009) and ESVi (30.6 ± 15.5 vs. 22.3 ± 7.6, p < 0.001) at follow-up.ConclusionIn optimally treated STEMI, dysfunction of remote myocardium assessed by LS: (1) is predicted by elevated NT-proBNP; (2) could be independent of CAD extent and infarct size; (3) is associated to worse LV morphological and functional indexes at follow-up.

BackgroudThe aim of this study was to assess the prognostic association of plasma levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) with clinical outcomes of patients with microvascular angina (MVA). Methods: In this international prospective cohort study of MVA by the Coronary Vasomotor Disorders International Study (COVADIS) group, we examined the association between plasma NT-proBNP levels and the incidence of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. Results: We examined a total of 226 MVA patients (M/F 66/160, 61.9 ± 10.2 [SD] yrs.) with both plasma NT-proBNP levels and echocardiography data available at the time of enrolment. The median level of NT-proBNP level was 94 pg/ml, while mean left ventricular ejection fraction was 69.2 ± 10.9 % and E/e’ 10.7 ± 5.2. During follow-up period of a median of 365 days (IQR 365–482), 29 MACEs occurred. Receiver-operating characteristics curve analysis identified plasma NT-proBNP level of 78 pg/ml as the optimal cut-off value. Multivariable logistic regression analysis revealed that plasma NT-proBNP level ≥ 78 pg/ml significantly correlated with the incidence of MACE (odds ratio (OR) [95 % confidence interval (CI)] 3.11[1.14–8.49], P = 0.001). Accordingly, Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with NT-proBNP ≥ 78 (log-rank test, P

Abstract The COVID-19 pandemic is impressively challenging the healthcare system. Several prognostic models have been validated but few of them are implemented in daily practice. The objective of the study was to validate a machine-learning risk prediction model using easy-to-obtain parameters to help to identify patients with COVID-19 who are at higher risk of death. The training cohort included all patients admitted to Fondazione Policlinico Gemelli with COVID-19 from March 5, 2020, to November 5, 2020. Afterward, the model was tested on all patients admitted to the same hospital with COVID-19 from November 6, 2020, to February 5, 2021. The primary outcome was in-hospital case-fatality risk. The out-of-sample performance of the model was estimated from the training set in terms of Area under the Receiving Operator Curve (AUROC) and classification matrix statistics by averaging the results of fivefold cross validation repeated 3-times and comparing the results with those obtained on the test set. An explanation analysis of the model, based on the SHapley Additive exPlanations (SHAP), is also presented. To assess the subsequent time evolution, the change in paO2/FiO2 (P/F) at 48 h after the baseline measurement was plotted against its baseline value. Among the 921 patients included in the training cohort, 120 died (13%). Variables selected for the model were age, platelet count, SpO2, blood urea nitrogen (BUN), hemoglobin, C-reactive protein, neutrophil count, and sodium. The results of the fivefold cross-validation repeated 3-times gave AUROC of 0.87, and statistics of the classification matrix to the Youden index as follows: sensitivity 0.840, specificity 0.774, negative predictive value 0.971. Then, the model was tested on a new population (n = 1463) in which the case-fatality rate was 22.6%. The test model showed AUROC 0.818, sensitivity 0.813, specificity 0.650, negative predictive value 0.922. Considering the first quartile of the predicted risk score (low-risk score group), the case-fatality rate was 1.6%, 17.8% in the second and third quartile (high-risk score group) and 53.5% in the fourth quartile (very high-risk score group). The three risk score groups showed good discrimination for the P/F value at admission, and a positive correlation was found for the low-risk class to P/F at 48 h after admission (adjusted R-squared = 0.48). We developed a predictive model of death for people with SARS-CoV-2 infection by including only easy-to-obtain variables (abnormal blood count, BUN, C-reactive protein, sodium and lower SpO2). It demonstrated good accuracy and high power of discrimination. The simplicity of the model makes the risk prediction applicable for patients in the Emergency Department, or during hospitalization. Although it is reasonable to assume that the model is also applicable in not-hospitalized persons, only appropriate studies can assess the accuracy of the model also for persons at home.

BackgroundThe 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.Materials and methodsConsecutive patients followed-up at our ACHD Outpatient Clinic from September 2014 to February 2021 were enrolled. Clinical characteristics and echocardiographic data were prospectively entered into a digitalized medical records database. VHD at the first evaluation was assessed and graded according to VHD guidelines. Clinical data at follow-up were collected. The study endpoint was the occurrence of cardiac mortality and/or unplanned cardiac hospitalization during follow-up.ResultsA total of 390 patients (median age 34 years, 49% males) 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 study composite endpoint occurred in 76 patients (19.5%). The cumulative endpoint-free survival was significantly lower in patients with S-VHD vs. patients with non-severe VHD (Log rank p < 0.001). At multivariable analysis, age and atrial fibrillation at first visit (p = 0.029 and p = 0.006 respectively), lower %Sat O2, higher NYHA class (p = 0.005 for both), lower LVEF (p = 0.008), and S-VHD (p = 0.015) were independently associated to the study endpoint. The likelihood ratio test demonstrated that S-VHD added significant prognostic value (p = 0.017) to a multivariate model including age, severe CHD, atrial fibrillation, %Sat O2, NYHA, LVEF, and right ventricle systolic pressure > 45 mmHg.ConclusionIn 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.

BackgroundMalignancies represent 15–50% of total causes of pericardial effusions (PE). Routine analyses recommended to be performed on pericardial fluid include general chemistry, cytology, polymerase chain reaction, and microbiological cultures. Multicolor flow cytometry (FC) is a laboratory test that already proved to be useful in the detection of lymphoproliferative and metastatic malignancies in pleural and peritoneal effusions, but current guidelines do not mention its use on PE to reach a diagnosis.MethodsOur institutional protocol foresees to routinely perform a multicolor FC analysis on pericardial fluid samples obtained by pericardiocentesis, in addition to other guidelines-recommended analyses. A sample of 15–30 ml is analyzed using a lyse and wash staining method using combination panels of antibodies, allowing to detect specific cellular subpopulations, analyzing tens to hundreds of thousands of cells in few seconds. The present manuscript aims to report our single-center experience with this diagnostic tool in patients presenting with PE requiring pericardiocentesis.ResultsRoutine use of multicolor FC on pericardial fluid samples in our institution allowed to reach a definite diagnosis of cardiac lymphomas in two patients presenting with otherwise unexplained severe PE. This resulted in immediate start of combined immunotherapy, with patients’ clinical improvement. At 6 months follow-up both patients are alive and presented a complete disease regression.ConclusionPreliminary evidence from routine use of multicolor FC on PE support that this is a promising tool to reach a rapid diagnosis of hematological malignancies with heart involvement, leading to a prompt initiation of targeted therapies.

Myocardial bridging (MB) is the most frequent congenital coronary anomaly in which a segment of an epicardial coronary artery takes a tunneled course under a bridge of the myocardium. This segment is compressed during systole, resulting in the so-called “milking effect” at coronary angiography. As coronary blood flow occurs primarily during diastole, the clinical relevance of MB is heterogeneous, being usually considered an asymptomatic bystander. However, many studies have suggested its association with myocardial ischemia, anginal symptoms, and adverse cardiac events. The advent of contemporary non-invasive and invasive imaging modalities and the standardization of intracoronary functional assessment tools have remarkably improved our understanding of MB-related ischemia, suggesting the role of atherosclerotic lesions proximal to MB, vasomotor disorders and microvascular dysfunction as possible pathophysiological substrates. The aim of this review is to provide a contemporary overview of the pathophysiology and of the non-invasive and invasive assessment of MB, in the attempt to implement a case-by-case therapeutic approach according to the specific endotype of MB-related ischemia.

IntroductionUnrecognized incomplete pulmonary vein (PV) isolation during the index procedure, can be a major cause of clinical recurrences of atrial fibrillation (AF) after cryoballoon (CB) ablation. We aimed to characterize the extension of the lesions produced by CB ablation and to assess the value of using an ultra-high resolution electroanatomic mapping (UHDM) system to detect incomplete CB lesions.Materials and methodsTwenty-nine consecutive patients from the CHARISMA registry undergoing AF ablation at four Italian centers were prospectively evaluated. The Rhythmia™ mapping system and the Orion™ (Boston Scientific) mapping catheter were used to systematically map the left atrium and PVs before and after cryoablation.ResultsA total of 116 PVs were targeted and isolated. Quantitative assessment of the lesions revealed a significant reduction of the antral surface area of the PV, resulting in an ablated area of 5.7 ± 0.7 cm2 and 5.1 ± 0.8 cm2 for the left PV pair and right PV pair, respectively (p = 0.0068). The mean posterior wall (PW) area was 22.9 ± 2 cm2 and, following PV isolation, 44.8 ± 6% of the PW area was ablated. After CB ablation, complete isolation of each PV was documented by the POLARMap™ catheter in all patients. By contrast, confirmatory UHDM and the Lumipoint™ tool unveiled PV signals in 1 out of 114 of the PVs (0.9%). Over 30-day follow-up, no major procedure-related adverse events were reported. After a mean follow-up of 333 days, 89.7% of patients were free from arrhythmia recurrence.ConclusionThe lesion extension achieved by the new CB ablation system involved the PV antrum, with less than 50% of the PW remaining untouched. The new system, with short tip and circular mapping catheter, failed to achieve PV isolation in only 0.9% of all PVs treated.Clinical trial registration[http://clinicaltrials.gov/], identifier [NCT03793998].

Abstract Aims Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes. Methods and results Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In‐hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long‐term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long‐term mortality (hazard ratio 2.12, 95% confidence interval 1.33–3.38; P = 0.002). Conclusions The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in‐hospital course and a worse long‐term outcome.

BackgroundWhile the importance of invasive physiological assessment (IPA) to choose coronary lesions to be treated is ascertained, its role after PCI is less established. We evaluated feasibility and efficacy of Physiology-guided PCI in the everyday practice in a retrospective registry performed in a single high-volume and “physiology-believer” center.Materials and methodsThe PROPHET-FFR study (NCT05056662) patients undergoing an IPA in 2015–2020 were retrospectively enrolled in three groups: Control group comprising patients for whom PCI was deferred based on a IPA; Angiography-Guided PCI group comprising patients undergoing PCI based on an IPA but without a post-PCI IPA; Physiology-guided PCI group comprising patients undergoing PCI based on an IPA and an IPA after PCI, followed by a physiology-guided optimization, if indicated. Optimal result was defined by an FFR value ≥ 0.90.ResultsA total of 1,322 patients with 1,591 lesions were available for the analysis. 893 patients (67.5%) in Control Group, 249 patients (18.8%) in Angiography-guided PCI Group and 180 patients (13.6%) in Physiology-guided PCI group. In 89 patients a suboptimal functional result was achieved that was optimized in 22 cases leading to a “Final FFR” value of 0.90 ± 0.04 in Angiography-Guided PCI group. Procedural time, costs, and rate of complications were similar. At follow up the rate of MACEs for the Physiology-guided PCI group was similar to the Control Group (7.2% vs. 8.2%, p = 0.765) and significantly lower than the Angiography-guided PCI Group (14.9%, p < 0.001), mainly driven by a reduction in TVRs.Conclusion“Physiology-guided PCI” is a feasible strategy with a favorable impact on mid-term prognosis. Prospective studies using a standardized IPA are warrant to confirm these data.

BackgroundCoronary microvascular dysfunction can be responsible for both stable angina and acute coronary syndrome (ACS). There are scarce data, however, about comparisons of clinical characteristics and outcomes of these 2 groups of patients.Materials and methodsWe studied 47 consecutive patients who underwent coronary angiography for angina syndromes and showed no obstructive stenosis. Patients were divided in 2 groups, according to their clinical presentation, i.e., stable angina (n = 21) or non-ST segment elevation ACS (NSTE-ACS; n = 26). An intracoronary acetylcholine (Ach) test was performed in 12 and 17 patients of the 2 groups, respectively. Angina status, assessed by Seattle Angina Questionnaire (SAQ), and clinical events were assessed after 1, 6, and 30 months. An exercise stress test was performed 1 month after discharge.ResultsClinical characteristics and exercise test results of the 2 groups were largely similar. Ach testing induced epicardial or microvascular spasm in 6 (50.0%) and 10 (58.8%) stable and NSTE-ACS patients, respectively (p = 0.72). Stable patients reported higher rates of angina, compared to NSTE-ACS patients, both at 1 (p = 0.04) and 30 months (81 vs. 50%, p = 0.036) of follow-up. SAQ scores were also lower in stable vs. NSTE-ACS patients. Ach testing results showed no association with clinical outcomes.ConclusionClinical characteristics and exercise and Ach testing results are similar in angina patients with no-obstructive coronary artery disease with a stable or NSTE-ACS presentation. Stable patients show a worse symptomatic outcome irrespective of Ach test results.

BackgroundAtrioventricular (AV) conduction disturbances requiring permanent pacemaker implantation (PPI) are a common complication after transcatheter aortic valve implantation (TAVI). However, a significant proportion of patients might recover AV conduction at follow-up.ObjectivesThe aim of our study was to evaluate the recovery of AV conduction by determination through Wenckebach point in patients with PPI and therefore identify patients who could benefit from device reprogramming to avoid unnecessary RV pacing.MethodsWe enrolled 43 patients that underwent PM implantation after TAVI at our Department from January 2018 to January 2021. PM interrogation was performed at follow-up and patients with native spontaneous rhythm were further assessed for AV conduction through WP determination.ResultsA total of 43 patients requiring a PM represented the final study population, divided in patients with severely impaired AV conduction (no spontaneous valid rhythm or WP < 100; 26) and patients with valid AV conduction (WP ≥ 100; 17). In the first group patients had a significantly higher number of intraprocedural atrioventricular block (AVB) (20 vs. 1, p < 0.005), showed a significant higher implantation depth in LVOT (7.7 ± 2.2 vs. 4.4 ± 1.1, p < 0.05) and lower ΔMSID (−0.28 ± 3 vs. −3.94 ± 2, p < 0.05).ConclusionAV conduction may recover in a significant proportion of patients. In our study, valve implantation depth in the LVOT and intraprocedural AV block are associated with severely impaired AV conduction. Regular PM interrogation and reprogramming are required to avoid unnecessary permanent right ventricular stimulation in patients with AV conduction recovery.

Cardiovascular disease is the major cause of morbidity and mortality in breast cancer survivors. Chemotherapy contributes to this risk. We aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel therapeutic targets. We studied arteries from postmenopausal women who had undergone breast cancer treatment using docetaxel, doxorubicin, and cyclophosphamide (NACT) and from women with no history of such treatment matched for key clinical parameters. We explored mechanisms in WT and Nox4–/– mice and in human microvascular endothelial cells. Endothelium-dependent, NO-mediated vasodilatation was severely impaired in patients after NACT, while endothelium-independent responses remained normal. This was mimicked by a 24-hour exposure of arteries to NACT agents ex vivo. When applied individually, only docetaxel impaired endothelial function in human vessels. Mechanistic studies showed that NACT increased inhibitory eNOS phosphorylation of threonine 495 in a Rho-associated protein kinase–dependent (ROCK-dependent) manner and augmented vascular superoxide and hydrogen peroxide production and NADPH oxidase activity. Docetaxel increased expression of the NADPH oxidase NOX4 in endothelial and smooth muscle cells and NOX2 in the endothelium. A NOX4 increase in human arteries may be mediated epigenetically by diminished DNA methylation of the NOX4 promoter. Docetaxel induced endothelial dysfunction and hypertension in mice, and these were prevented in Nox4–/– mice and by pharmacological inhibition of Nox4 or Rock. Commonly used chemotherapeutic agents and, in particular, docetaxel alter vascular function by promoting the inhibitory phosphorylation of eNOS and enhancing ROS production by NADPH oxidases.

BackgroundTakotsubo syndrome (TTS) is an emerging disease characterized by an acute and reversible myocardial dysfunction which may have an influence on clinical status and prognosis. Despite extensive research, its pathophysiology has not been completely elucidated; among other hypothesis, a heart-brain interaction has been proposed.MethodsThe aim of this study was to assess the impact of psychiatric disorders and of some personality types on the pathogenesis of TTS. We conducted a retrospective observational case-control study. We enrolled a total of 50 patients, 25 with a previous diagnosis of TTS and 25 patients with a history of acute coronary syndrome (ACS), that underwent a comprehensive lifetime psychiatric assessment.ResultsWe found no significant difference between TTS and ACS patients in cardiovascular risk profile. The frequency of lifetime psychiatric disorders was significantly greater in TTS. In particular, in the univariate analysis, TTS group showed a higher prevalence of mood disorders (Major Depressive Disorder, Bipolar Disorder, Dysthymia; 16 vs. 2, P < 0.001) and anxiety disorder (Generalized Anxiety Disorder, Panic Disorder, Agoraphobia; 20 vs. 8, P = 0.001) compared with ACS group. There was also a significant tendency in TTS patients to psychotropic medication use, substance abuse, and psychologist or psychiatrist consulting. However, there was no difference between the groups in previous stressful events and Type D personality. Moreover, the multivariate analysis showed that mood disorders were independently associated with TTS (OR 16.9, 95% CI, 2.2–127).ConclusionOur study demonstrated that pre-existing anxiety disorders and mostly mood disorders were significantly higher in TTS patients than in ACS group, suggesting the role of psychiatric disorders as possible pathophysiological substrate of TTS.

AimsHuman epicardial adipose tissue, a dynamic source of multiple bioactive factors, holds a close functional and anatomic relationship with the epicardial coronary arteries and communicates with the coronary artery wall through paracrine and vasocrine secretions. We explored the hypothesis that T-cell recruitment into epicardial adipose tissue (EAT) in patients with non-ST segment elevation myocardial infarction (NSTEMI) could be part of a specific antigen-driven response implicated in acute coronary syndrome onset and progression.Methods and ResultsWe enrolled 32 NSTEMI patients and 34 chronic coronary syndrome (CCS) patients undergoing coronary artery bypass grafting (CABG) and 12 mitral valve disease (MVD) patients undergoing surgery. We performed EAT proteome profiling on pooled specimens from three NSTEMI and three CCS patients. We performed T-cell receptor (TCR) spectratyping and CDR3 sequencing in EAT and peripheral blood mononuclear cells of 29 NSTEMI, 31 CCS, and 12 MVD patients. We then used computational modeling studies to predict interactions of the TCR beta chain variable region (TRBV) and explore sequence alignments. The EAT proteome profiling displayed a higher content of pro-inflammatory molecules (CD31, CHI3L1, CRP, EMPRINN, ENG, IL-17, IL-33, MMP-9, MPO, NGAL, RBP-4, RETN, VDB) in NSTEMI as compared to CCS (P < 0.0001). CDR3-beta spectratyping showed a TRBV21 enrichment in EAT of NSTEMI (12/29 patients; 41%) as compared with CCS (1/31 patients; 3%) and MVD (none) (ANOVA for trend P < 0.001). Of note, 11/12 (92%) NSTEMI patients with TRBV21 perturbation were at their first manifestation of ACS. Four patients with the first event shared a distinctive TRBV21-CDR3 sequence of 178 bp length and 2/4 were carriers of the human leukocyte antigen (HLA)-A*03:01 allele. A 3D analysis predicted the most likely epitope able to bind HLA-A3*01 and interact with the TRBV21-CDR3 sequence of 178 bp length, while the alignment results were consistent with microbial DNA sequences.ConclusionsOur study revealed a unique immune signature of the epicardial adipose tissue, which led to a 3D modeling of the TCRBV/peptide/HLA-A3 complex, in acute coronary syndrome patients at their first event, paving the way for epitope-driven therapeutic strategies.

IntroductionStereotactic arrhythmia radioablation (STAR) is a novel technique for the ablation of ventricular tachycardia in patients with contraindications to standard procedures, i.e., radiofrequency ablation.Case presentationWe report the case of a 73-year-old man with non-ischemic dilated cardiomyopathy and recurrent VT episodes. Electroanatomic mapping showed VT prevalently of epicardial origin, but direct epicardial access through subxyphoid puncture could not be performed due to pleuropericardial adhesions from a past history of chemical pleurodesis. STAR was performed, with no VT recurrence at 6 months follow-up.ConclusionsPrevious experiences with STAR have demonstrated its importance in the management of patients with refractory VT in whom other ablation strategies were not successful. Our case report highlights the use of STAR as a second choice in a patient with an unfavorable VT anatomical location and technical limitations to an optimal radiofrequency ablation. Moreover, it confirms STAR's effectiveness in the ablation of complex transmural lesions, which are more often associated with non-ischemic structural heart disease.

BackgroundDespite continuous advancement in the field, heart failure (HF) remains the leading cause of hospitalization among the elderly and the overall first cause of hospital readmission in developed countries. Implantable hemodynamic monitoring is being tested to anticipate the clinical exacerbation onset, potentially preventing an emergent acute decompensation. To date, only pulmonary artery pressure (PAP) sensor received the approval to be implanted in symptomatic heart failure patients with reduced ejection fraction. However, PAP's indirect estimation of left ventricular filling pressure can be inaccurate in some contexts.MethodsThe VECTOR-HF study (NCT03775161) is examining the safety, usability and performance of the V-LAP system, a latest-generation device capable of continuously monitoring left atrial pressure (LAP). In our center, five advanced HF patients have been enrolled. After confirmation of the transmitted data reliability, LAP trends and waveforms have guided therapy optimization. The aim of this work is to share clinical insights from our center preliminary experience with V-LAP application.ResultsOver a median follow-up time of 18 months, LAP–based therapy optimization managed to reduce intracardiac pressure over time and no hospital readmission occurred. This result was paralleled by an improvement in both functional capacity (6MWT distance 352.5 ± 86.2 meters at baseline to 441.2 ± 125.2 meters at last follow-up) and quality of life indicators (KCCQ overall score 63.82 ± 16.36 vs. 81.92 ± 9.63; clinical score 68.47 ± 19.48 vs. 83.70 ± 15.58).ConclusionPreliminary evidence from V-LAP application at our institution support a promising efficacy. However, further study is needed to confirm the technical reliability of the device and to exploit the clinical benefit of left-sided hemodynamic remote monitoring.

Background A multidisciplinary approach might be pivotal for the management of patients with valvular heart disease (VHD), but clinical outcome data are lacking. Methods and Results At our institution, since 2014, internal guidelines recommended heart team consultations for patients with VHD. The clinical/echocardiographic characteristics, treatment recommendations, performed treatment, and early clinical outcomes of consecutive, hospitalized patients with VHD undergoing heart team evaluation were collected. Surgical risk was prospectively assessed by the EuroSCORE II and STS‐PROM. The primary end point of the study was early mortality. A total of 1004 patients with VHD with high clinical complexity (mean age, 75 years; mean EuroSCORE II, 9.4%; mean STS‐PROM, 5.6%; 48% ischemic heart disease; 29% chronic kidney disease, 9% oncologic/hematologic diseases) were enrolled. The heart team recommended an interventional treatment for 807 (80%) patients and conservative management for 197 (20%) patients. Management crossovers occurred in only 5% of patients. The recommended intervention was cardiac surgery for 230 (23%) patients, percutaneous treatment in 516 (51%) patients, and hybrid treatment in 61 (6%) patients. Early mortality occurred in 24 patients (2.4%) and was independently predicted by aortic stenosis, left ventricular ejection fraction, pulmonary artery systolic pressure, and conservative management recommendation. In patients referred to treatment, observed early mortality (1.7%) was significantly lower (P

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.

Abstract Endothelial erosion of atherosclerotic plaques is the underlying cause of approximately 30% of acute coronary syndromes (ACS). As the vascular endothelium is profoundly affected by the haemodynamic environment to which it is exposed, we employed computational fluid dynamic (CFD) analysis of the luminal geometry from 17 patients with optical coherence tomography (OCT)-defined plaque erosion, to determine the flow environment permissive for plaque erosion. Our results demonstrate that 15 of the 17 cases analysed occurred on stenotic plaques with median 31% diameter stenosis (interquartile range 28–52%), where all but one of the adherent thrombi located proximal to, or within the region of maximum stenosis. Consequently, all flow metrics related to elevated flow were significantly increased (time averaged wall shear stress, maximum wall shear stress, time averaged wall shear stress gradient) with a reduction in relative residence time, compared to a non-diseased reference segment. We also identified two cases that did not exhibit an elevation of flow, but occurred in a region exposed to elevated oscillatory flow. Our study demonstrates that the majority of OCT-defined erosions occur where the endothelium is exposed to elevated flow, a haemodynamic environment known to evoke a distinctive phenotypic response in endothelial cells.

Background: Cardiovascular (CV) diseases are a cause of increased long-term morbidity and mortality in childhood cancer survivors (CCSs) treated with anthracyclines. These drugs may affect not only the heart, but also the vascular system. Left ventricular-arterial coupling (LVAC) represents a reliable parameter of altered ventricular and vascular performance, with validated prognostic value and never investigated in this setting. Aim of this study was to assess, in CCSs and matched controls, LVAC changes, performed with different echocardiographic modalities, and their relationship with endothelial function. Methods: Twenty survivors treated with anthracyclines for childhood malignancies and a matched control group of 20 healthy subjects were enrolled. Arterial elastance (Ea), end-systolic elastance (Ees), Ea/Ees ratio, as well as three-dimensional (3D) LVAC (assessed by measurement of End Systolic Volume [ESV]/Stroke Volume [SV] ratio) were performed at rest. Endothelial function was evaluated by measurement of flow-mediated dilatation (FMD) of the brachial artery. Results: 3D SV and 3D ESV/SV ratio resulted respectively significantly lower and higher in CCSs than in controls, while Ea, Ees and Ea/Ees ratio were not different among groups. A positive correlation between 3D ESV/SV ratio and cumulative anthracycline doses, as well as with time after drug exposure were also found. Mean FMD was similar in CCSs and controls (8.45 ± 1.79 versus 9.41 ± 3.41, p = 0.34). Conclusions: In conclusion, conventional LVAC parameters were not shown to be significantly different between CCSs and controls; however, 3D SV and LVAC were significantly impaired in our population. In these patients, endothelial function was comparable to controls. Larger validation studies are therefore needed.

Abstract Aims In Fabry cardiomyopathy, left ventricular outflow tract obstruction mimicking hypertrophic cardiomyopathy is a very rare finding, with few cases reported and successfully treated with cardiac surgery. In our population of patients with Fabry disease and severe left ventricular hypertrophy (LVH) at the time of diagnosis, we observed an evolution towards a midventricular obstructive phenotype. Methods and results We present a case series of three classically affected Fabry male patients with significant diagnostic delay and severe cardiac involvement (maximal wall thickness >20 mm) at first evaluation. All patients developed midventricular obstructive form over time despite prompt initiation and optimal compliance to enzyme replacement therapy. The extension and distribution of the LVH, involving the papillary muscles, was the main mechanism of obstruction, unlike the asymmetric septal basal hypertrophy and the mitral valve abnormalities commonly seen as substrate of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. Conclusions Fabry cardiomyopathy can evolve over time towards a midventricular obstructive form due to massive LVH in classically affected men with significant diagnostic delay and severe LVH before enzyme replacement therapy initiation. This newly described cardiac phenotype could represent an adverse outcome of the disease.

Acute Coronary Syndromes (ACS) with plaque erosion display dysregulated hyaluronan metabolism, with increased hyaluronidase-2 (HYAL2) expression. However, the expression and the role of this enzyme on platelets has never been explored. We evaluated the platelet’s HYAL2 (pltHYAL2) levels on I) stable angina (SA) and II) ACS patients, furtherly sub-grouped in Intact-Fibrous-Cap (IFC) and Ruptured-Fibrous-Cap (RFC), according to Optical Coherence Tomography. We assessed the HYAL2 role through an in vitro model setting of co-cultured monocytes and platelets, before and after treatment with low-molecular-weight hyaluronic acid (HA) as pro-inflammatory stimulus and with or without HYAL2-antibody to inhibit HYAL2 activity. ACS patients exhibit higher pltHYAL2 levels comparing to SA, with the higher expression for IFC group. The addition of HYAL2-antibody significantly reduced the percentage of monocyte-platelet binding, suggesting that pltHYAL2 enrichment at the site of the culprit lesion is a key mediator in the systemic thrombo-inflammatory status of ACS presenting with plaque erosion.

Abstract Aims Right ventricular hypertrophy (RVH) is a common finding in Anderson–Fabry disease (AFD), but the prognostic role of right ventricular (RV) involvement has never been assessed. The aim of our study was to evaluate the prognostic significance of RVH and RV systolic function in AFD. Methods and results Forty‐five AFD patients (56% male patients) with extensive baseline evaluation, including assessment of RVH and RV systolic function, were followed‐up for an average of 51.2 ± 11.4 months. RV systolic function was assessed by standard and tissue Doppler echocardiography. Cardiovascular events were defined as new‐onset atrial fibrillation (AF), sustained ventricular arrhythmias, heart failure, or pacemaker/implantable cardioverter defibrillator implantation; renal events were defined as progression to dialysis and/or renal transplantation or significant worsening of glomerular filtration rate; and cerebrovascular events were defined as transient ischaemic attack or stroke. Fourteen patients (31.1%) presented RVH, while RV systolic function was normal in all cases. During the follow‐up period, 13 patients (28.8%, 11 male) experienced 18 major events, including two deaths. Cardiovascular events occurred in eight patients (17.7%). The most common event was pacemaker/implantable cardioverter defibrillator implantation (six patients, 13.3%), followed by AF (three cases, 6.6%). Only one case of worsening New York Heart Association class (from II to III and IV) was observed. Ischaemic stroke occurred in three cases (6.6%). Renal events were recorded in three patients (6.6%). At univariate analysis, several variables were associated with the occurrence of events, including RVH (HR: 7.09, 95% CI: 2.17 to 23.14, P = 0.001) and indexes of RV systolic function (tricuspid annular plane systolic excursion HR: 0.77, 95% CI: 0.62 to 0.96, P = 0.02; and RV tissue Doppler systolic velocity HR: 0.76, 95% CI: 0.61 to 0.93, P = 0.01). At multivariate analysis, proteinuria (HR:8.3, 95% CI: 2.88 to 23.87, P

Abstract Coronary fibromuscular dysplasia is uncommon, and even rarer its unstable and recurrent course. We present the unique case of a 52‐year‐old woman who underwent in total 12 coronary angiographies and three percutaneous coronary intervention within 24 months because of repetitive acute coronary syndromes due to refractory spasm, dissection, restenosis all leading to end‐stage heart failure, and heart transplantation. The patient died 12 days after the heart transplantation complicated by intraoperative acute thrombotic occlusion of left anterior descending artery of the graft despite normal pretransplant coronary angiography. Autopsy of the recipient heart confirmed coronary fibromuscular dysplasia with massive intimal hyperplasia and restenosis.

Abstract Background Danon disease (OMIM 300257) is an X-linked lysosomal storage disorder, characterized by hypertrophic cardiomyopathy (HCM), skeletal myopathy, variable intellectual disability, and other minor clinical features. This condition accounts for ~ 4% of HCM patients, with a more severe and early onset phenotype in males, causing sudden cardiac death (SCD) in the first three decades of life. Genetic alterations in the LAMP2 gene are the main cause of this inherited fatal condition. Up to date, more than 100 different pathogenic variants have been reported in the literature. However, the majority of cases are misdiagnosed as HCM or have a delay in the diagnosis. Case presentation Here, we describe a young boy with an early diagnosis of HCM. After 2 episodes of ventricular fibrillation within 2 years, genetic testing identified a novel LAMP2 pathogenic variant. Subsequently, further clinical evaluations showing muscle weakness and mild intellectual disability confirmed the diagnosis of Danon disease. Conclusions This report highlights the role of genetic testing in the rapid diagnosis of Danon disease, underscoring the need to routinely consider the inclusion of LAMP2 gene in the genetic screening for HCM, since an early diagnosis of Danon disease in patients with a phenotype mimicking HCM is essential to plan appropriate treatment, ie cardiac transplantation.

AimsThe “early repolarization” (ER) pattern and J wave are frequent findings on standard ECG. Controversial data have recently been reported about their prognostic implications in healthy subjects, but no longitudinal prospective study specifically designed to investigate their long-term prognostic value has hitherto been published.Methods and ResultsWe prospectively enrolled 4,176 consecutive subjects with no evidence of cardiovascular disease who were referred for standard ECG recording for routine check-ups or pre-operative assessments for non-cardiovascular surgery. ECGs were prospectively assessed for the presence of ER/J wave. A 10-year follow-up was available for 3,937 patients (94.3%), 660 of whom (16.8%) showed ER/J wave whereas 3,277 did not. A total of 644 deaths occurred (16.3%), 116 (2.95%) of which were attributed to cardiovascular causes. Both total and cardiovascular mortality adjusted for clinical and laboratory variables did not differ significantly between patients with vs. without ER/J wave (HR 0.94; 95% CI 0.75–1.19; p = 0.63 and HR 0.61; 95% CI 0.31–1.21; p = 0.16, respectively). No significant association with total and cardiovascular mortality was also found in pre-specified analyses for ER and J wave alone, ER/J wave detected in specific ECG regions (i.e., inferior, lateral, precordial), and type of J wave (notched or slurred).ConclusionIn this specifically designed prospective study of individuals without any evidence of cardiovascular disease, we found no significant association of ER/J wave with the risk of the total as well as cardiovascular mortality during long-term follow-up.

Despite the recent innovations in cardiovascular care, atherothrombosis is still a major complication of acute coronary syndromes (ACS). We evaluated the involvement of the CD31 molecule in thrombotic risk through the formation of monocyte-platelet (Mo-Plt) aggregates in patients with ACS with no-ST-segment elevation myocardial infarction (NSTEMI) on top of dual anti-platelet therapy (DAPT). We enrolled 19 control (CTRL) subjects, 46 stable angina (SA), and 86 patients with NSTEMI, of which, 16 with Intact Fibrous Cap (IFC) and 19 with Ruptured Fibrous Cap (RFC) as assessed by the Optical Coherence Tomography (OCT). The expression of CD31 on monocytes and platelets was measured. Following the coronary angiography, 52 NSTEMIs were further stratified according to thrombus grade (TG) evaluation. Finally, a series of ex vivo experiments verified whether the CD31 participates in Mo-Plt aggregate formation. In patients with NSTEMI, CD31 was reduced on monocytes and was increased on platelets, especially in NSTEMI presented with RFC plaques compared to those with IFC lesions, and in patients with high TG compared to those with zero/low TG. Ex vivo experiments documented an increase in Mo-Plt aggregates among NSTEMI, which significantly decreased after the CD31 ligation, particularly in patients with RFC plaques. In NSTEMI, CD31 participates in Mo-Plt aggregate formation in spite of optimal therapy and DAPT, suggesting the existence of alternative thrombotic pathways, as predominantly displayed in patients with RFC.

Electronic cigarettes use is a growing trend in contemporary societies, with the propensity to compete with traditional tobacco smoking. Some preclinical studies demonstrated the toxic and detrimental effects of electronic cigarettes liquid components. Its impact on human health remains unknown and insufficiently studied. While some studies suggest that electronic cigarettes use might be associated with endothelial dysfunction, impaired platelet function and increased risk of adverse clinical events, other studies did not confirm these findings and epidemiological data mostly suggest that the use of electronic cigarettes appears to be safer than that of traditional tobacco cigarettes. This article provides an up-to-date overview of the current state of knowledge regarding electronic cigarettes and their impact on human health, with special emphasis on their effect on cardiovascular diseases.

Study objective: The Coronary Vasomotor Disorders International Study Group (COVADIS) invited leading experts to address strategies to enhance our clinical understanding of INOCA with an emphasis on the management of coronary vasomotor disorders. Design: Under-recognition of coronary vasomotor disorders, distinguishing different presentations of angina due to vasospasm and/or abnormal microvascular vasodilatation, developing invasive/non-invasive testing and treatment protocols, integrating diagnostic protocols into cardiologists' workflow and trials to inform guideline development were identified as key knowledge gaps and will be briefly addressed in this Viewpoint article. Setting: Virtual international meeting. Participants: Leading international experts in ischemic heart disease with no obstructive coronary artery disease. Interventions: None. Main outcome measures: None. Results: Topics discussed include: 1. Obstructive epicardial disease, functional vasospasm and microvascular disorders; 2. Under-recognition of coronary vasomotor disorders in clinical practice; 3. Complexity of coronary vasomotor disorders; 4. Understanding different presentations - vasospastic disease and microvascular angina; 5. Invasive/noninvasive testing and treatment protocols for vasospasm and microvascular angina assessment; 6. Treatment challenges; 7. Integrating diagnostic protocols into cardiologists' workflow; 8. The path forward to advance our approach to managing myocardial ischemia. Conclusions: Obstructive epicardial disease, functional vasospasm and microvascular disorders often co-exist and contribute to myocardial ischemia. Under-recognition, the complexity of coronary vasomotor disorders, understanding different presentations, testing and treatment protocols, treatment challenges, and integrating diagnostic protocols into cardiologists' workflow all contribute to the path forward to advance our management of myocardial ischemia for improved patient outcomes.

Background A recent study reported that the outcome of patients with plaque erosion treated with stenting is poor when the underlying plaque is lipid rich. However, the detailed phenotype of patients with plaque erosion, particularly as related to different age groups, has not been systematically studied. Methods and Results Patients with acute coronary syndromes caused by plaque erosion were selected from 2 data sets. Demographic, clinical, angiographic, and optical coherence tomography findings of the culprit lesion were compared between 5 age groups. Among 579 erosion patients, male sex and current smoking were less frequent, and hypertension, diabetes, and chronic kidney disease were more frequent in older patients. ST‐segment–elevation myocardial infarction was more frequent in younger patients. Percentage of diameter stenosis on angiogram was greater in older patients. The prevalence of lipid‐rich plaque (27.3% in age

The evaluation of monocyte subset distribution among acute coronary syndrome (ACS) patients according to culprit coronary plaque morphology has never been explored. We evaluated whether there were significant differences in frequency of circulating monocyte subsets isolated from ACS patients according to optical coherence tomography (OCT) investigation of plaque erosion and rupture. We enrolled 74 patients with non-ST-elevation ACS (NSTE-ACS), 21 of them underwent OCT investigation of the culprit coronary plaque and local macrophage infiltration (MØI) assessment. As control, we enrolled 30 chronic coronary syndrome (CCS) patients. We assessed the frequency of monocyte subsets in the whole study population, in reliance on their CD14 and CD16 expression (classical, CM: CD14++CD16–; intermediates, IM: CD14++CD16+; non-classical, NCM: CD14+CD16++). Then, we tested the effect of lipopolysaccharide (LPS) (a CD14 ligand) on peripheral blood mononuclear cells (PBMCs) of NSTE-ACS patients, quantifying the inflammatory cytokine levels in cell-culture supernatants. Our data proved that monocyte subsets isolated from NSTE-ACS patients represent a peculiar biological signature of the pathophysiological mechanism lying beneath atherosclerotic plaque with a ruptured fibrous cap (RFC) as compared with plaque erosion. Moreover, the magnitude of LPS-mediated effects on IL-1β, IL-6, and IL-10 cytokine release in cell-culture supernatants appeared to be greater in NSTE-ACS patients with RFC. Finally, we described a fourth monocyte population never explored before in this clinical setting (pre-classical monocytes, PCM: CD14+CD16–) that was prevalent in NSTE-ACS patients as compared with CCS and, especially, in patients with RFC and culprit plaque with MØI.