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Funding Acknowledgements Type of funding sources: None. Background Catheter ablation (CA) improves prognosis in patients with electrical storm (ES). However, its effectiveness and timing in patients with ventricular tachycardia and appropriate ICD therapies remain a matter of debate. Purpose Our aim was to investigate whether patients with history of discrete ventricular tachycardia episodes had different clinical features and outcome compared to patients with ES as first arrhythmic occurrence. Methods We enrolled 57 consecutive patients undergoing CA for ES and collected clinical, echocardiographic and electroanatomic mapping data. The primary end point was a composite of death from any cause and recurrences of sustained VT or ventricular fibrillation, appropriate ICD therapy, or ES. Results During a median follow up of 39 months, 28 patients (49%) met the primary end point of arrhythmic recurrence or death from any cause. There were no significant differences between clinical, electrocardiographic and echocardiographic parameters in the two groups. Regarding ICD therapies, patients with who met the primary end point had a higher number of ATP/shock episodes preceding the ES event: 15 (52%) vs 25 (89%), p=0.002. At Cox regression analysis, NIDCM, previous ATP and/or shock and ≥3 ATP were associated with arrhythmic recurrences and/or death. At multivariate analysis, ≥3 ATP was the only predictor that met statistical significance for the primary end point: HR was 30.41, CI 4.42 – 209.12, p=0.001. When dividing our population in patients and without ventricular arrhythmias (VAs) with appropriate device intervention before ES, thoses with VAs arrhythmias before ES had a higher percentage of presence of late potentials (80% vs 55%, p=0.041) and a greater unipolar scar (59.2±41.6 vs 30.2±21.6, p=0.001). At univariate analysis the presence of late potentials was associated with ventricular arrhythmias before ES (OR 3.33, CI 1.03-10.84, p=0.045). Conclusions CA in patients with a long arrhythmia history, recurrent ICD therapies and presence of late potentials at electroanatomic mapping, may yield worse outcomes and therefore our results support an early referral for CA of VT to improve prognosis in these subjects.

Background Despite appropriate revascularization strategies, a significant number of patients with myocardial infarction (MI) develop ischemic heart failure suggesting that breakthrough therapies are yet to be approved in this setting. Methylation of non-histone proteins is emerging as a central regulatory mechanism in health and disease. The methyltransferase SETD7 has been shown to methylate and alter the function of a variety of proteins in vitro, however, its function in the heart is poorly understood. Purpose To determine the role of SETD7 in myocardial ischemic injury. Methods Neonatal rat ventricular myocytes (NRVM) were exposed to normal glucose levels or glucose deprivation (GD) for 15 h, in the presence of the selective SETD7 inhibitor (R)-PFI-2 or its inactive enantiomer (S)-PFI-2. Western blot and real-time PCR were employed to investigate the effects of energy stress on SETD7 and the Hippo pathway, while apoptosis and oxidative stress were assessed by Caspase-3 activity assay and mitoSOX staining. YAP transcriptional activity was assessed by chromatin immunoprecipitation assay (ChIP) while its localization and methylation were examined by confocal microscopy and immunoblotting, respectively. SETD7 knockout (SETD7−/−) mice and wild-type (WT) littermates underwent myocardial ischemia-reperfusion (I/R) injury (1h coronary ligation /24 h of reperfusion) followed by assessment of cardiac function by echocardiography. Left ventricular (LV) myocardial samples were collected from I/R mice and patients with ischemic cardiomyopathy (ICM), and isolated cardiomyocytes were treated with (R)-PFI-2. Finally, SETD7 expression was also assessed in peripheral blood mononuclear cells (PBMCs) from patients with ST-elevation MI (STEMI). Results SETD7 was activated upon energy deprivation in cultured NRVMs and methylated YAP, leading to its cytosolic retention and impaired transcription of antioxidant genes MnSOD and CAT. Pharmacological inhibition of SETD7 by (R)-PFI-2 restored YAP nuclear localization thus preventing mitochondrial reactive oxygen species (mtROS) and apoptosis. SETD7 deletion in mice attenuated I/R injury, mtROS and LV dysfunction by restoring YAP-dependent transcriptional programs. SETD7/YAP dysregulation was also observed in LV specimens from ICM patients. Moreover, in cardiomyocytes isolated from I/R mice and ICM patients, (R)-PFI-2 restored YAP nuclear localization, prevented mtROS accumulation while improving myofibrillar protein contractility and Ca2+ sensitivity. Finally, SETD7 was upregulated in PBMCs from STEMI patients and negatively correlated with the expression of MnSOD and CAT. Conclusions SETD7-dependent methylation of YAP is an important mechanism underpinning myocardial oxidative stress and apoptosis during ischemia. Pharmacological modulation of SETD7 by (R)-PFI-2 may represent a potential therapeutic approach to prevent myocardial ischemic damage through modulation of the Hippo pathway. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Zurich

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 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 whole body insulin sensitivity, myocardial perfusion, and metabolism in patients with T2D without HF. Research design and 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) or placebo. Whole body glucose uptake (WBGU) and myocardial glucose uptake (MGU) were measured with PET/CT with FDG during euglycemic hyperinsulinemic clamp. Stress (i.v. adenosine infusion) and resting myocardial blood flow (MBF) and myocardial flow reserve (MFR) were calculated by PET/CT with 13N-ammonia. Results 16 patients were randomized (8 dapagliflozin; 8 placebo). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). Dapagliflozin significantly improved MFR (2.56±0.26 vs 3.59±0.35) compared with placebo group (2.34±0.21 vs 2.38±0.24; p for interaction =0.001) and was associated to a reduction of resting MBF corrected for cardiac workload (p=0.045). A trend toward an increase in stress MBF was also detected (p=0.058). Moreover, in dapagliflozin group we observed an increase of WBGU of borderline statistical significance (p=0.06) and no effects on MGU (p=0.41). Conclusions At the best of our knowledge, our study, for the first time, demonstrated that SGLT-2 inhibition increases MFR in T2D patients. The data presented provide a new potential explanation of cardiovascular benefits with SGLT-2i as they make patients more tolerant to the detrimental impact of obstructive coronary atherosclerosis on MFR. Funding Acknowledgement Type of funding sources: None.

Aims Although the importance of microvascular angina (MVA) has been emerging, prognostic biomarkers for MVA remain to be developed. We thus aimed to examine whether plasma level of N-terminal prohormone of brain natriuretic peptide (NT-pro BNP) could predict the prognosis of MVA patients. Methods In the international prospective cohort study of MVA patients by the Coronary Vasomotor Disorders International Study (COVADIS) group, we evaluated the association between plasma level of NT-pro BNP 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] years) with both plasma NT-pro BNP levels and echocardiographic data in the COVADIS study. Plasma NT-pro BNP level was elevated (median 94 pg/ml, IQR 45–190) while mean LVEF (69.2±10.9%) and E/e' (10.7±5.2) were almost normal. During follow-up period of a median of 365 days (IQR 365–482), 29 MACEs occurred. ROC curve analysis identified plasma NT-pro BNP level of 78 pg/ml as the optimal cut-off value. Multivariable logistic regression analysis revealed that plasma NT-pro BNP 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=0.03). When divided into 2 groups by NT-pro BNP 78 pg/ml, the Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with NT-pro BNP ≥78 (log lank, P=0.03) (Figure). Conclusions These results indicate that plasma NT-pro BNP level is a novel prognostic biomarker for MVA patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Japan Heart Foundation

Background Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder characterized by airflow limitation, persistent respiratory symptoms and chronic lung inflammation. Previous studies reported a robust relationship between COPD and coronary artery disease (CAD). Local and systemic inflammation, known to play a role in atherosclerosis development, has been reported in patients with COPD, and has been proposed as one of the possible pathogenetic factors linking COPD and CAD. However, data on atherosclerotic coronary pattern and coronary inflammation in COPD patients are lacking. Purpose To study the characteristics of atherosclerotic coronary plaques and local inflammation by using optical coherence tomography (OCT) in COPD patients presenting with acute coronary syndromes (ACS). Methods ACS patients undergoing intracoronary OCT imaging of the culprit vessel were retrospectively identified. Coronary plaque characteristics and OCT-defined macrophage infiltration (MØI) were assessed by OCT. ACS patients were divided into 2 groups according to the presence or the absence of an established diagnosis of COPD, and coronary plaque features and MØI both at the culprit plaque site and along the culprit vessel were compared between the two groups. Results Among 146 ACS patients (mean age, 66,1±12,7 years, 109 males), 47 (32,2%) had COPD. Patients with COPD were older, were more frequently on therapy with an angiotensin receptor blocker, had lower hemoglobin, total cholesterol and triglycerides levels, and had higher serum creatinine levels. The prevalence of different mechanisms of ACS were similar between COPD and noCOPD patients (plaque rupture: 57,4% vs. 45,4%, plaque erosion: 23,4% vs. 32,3%, calcified plaque: 19,1% vs. 22,2%, respectively, overall p=0,381). OCT analysis of plaque microstructures showed that COPD patients had significantly higher prevalence of MØI (78,7% vs. 54,4%, p=0,005), thin cap fibroatheroma (TCFA) (48,9% vs. 22,2%, p=0,001), spotty calcium (68,1% vs. 26,3%, p Conclusions In ACS patients undergoing OCT imaging of the culprit vessel, COPD was an independent predictor of local plaque inflammation and plaque vulnerability both at the culprit site and along the culprit vessel. Our results may suggest that a higher inflammatory milieu in COPD patients might enhance local coronary inflammation, promoting CAD development and plaque vulnerability. Funding Acknowledgement Type of funding sources: None.

Background Whether revascularization reduces ischemic events and improves prognosis in patients with chronic coronary artery syndrome (CCS) without left main (LM) disease or reduced left ventricle ejection fraction (LVEF) remains a topic of debate. Nevertheless, the impact of revascularization on outcomes in patients with CCS may be influenced by the revascularization strategy adopted. Purpose We aimed at evaluating the comparative effects of different revascularization strategies in patients with CCS. Methods A total of 18 randomized controlled trials including angiography-guided percutaneous coronary intervention (PCI), physiology-guided PCI and coronary artery bypass graft (CABG), were included. Effect estimates included direct comparisons for all treatments and direct and indirect evidence were in agreement for all included outcomes, fulfilling the consistency assumption. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were used to adjust outcomes according to follow-up durations. Medical therapy was used as reference strategy. Results Compared with medical therapy, at a mean follow-up of 5.1 years, all revascularization strategies were associated with a reduction of the primary endpoint, as defined in each trial, the extent of which was modest with angiography-guided PCI (IRR 0.86, 95% CI 0.75–0.99) and greater with physiology-guided PCI (IRR 0.60, 95% CI 0.47–0.77) and CABG (IRR 0.58, 95% CI 0.48–0.70). Moreover, angiography-guided PCI was associated with increased primary endpoint compared to physiology-guided PCI (IRR 1.43, 95% CI 1.14–1.79) and CABG (IRR 1.49, 95% CI 1.27–1.74). CABG was the only strategy associated with reduced myocardial infarction (IRR 0.68, 95% CI 0.52–0.90), cardiovascular death (IRR 0.76, 95% CI 0.64–0.89), and all-cause death (IRR 0.87, 95% CI 0.77–0.99), but increased stroke (IRR 1.69, 95% CI 1.04–2.76). Results were consistent at secondary analysis exploring the impact on outcomes of baseline characteristics, such as 3-vessel disease, diabetes mellitus, year of publication or stents used. Conclusions In CCS patients without LM disease or reduced LVEF, physiology-guided PCI and CABG were associated with better outcomes than angiography-guided PCI. Compared with medical therapy, CABG was the only revascularization strategy associated with a reduction of myocardial infarction and death rates, at the cost of higher risk of stroke. Funding Acknowledgement Type of funding sources: None.

Background Whether the addition of percutaneous microaxial flow pump Impella to venoarterial extracorporeal membrane oxygenation (VA-ECMO) as left ventricle unloading strategy is effective in improving outcomes compared to VA-ECMO alone is still to be proved. Purpose Aim of this systematic review and meta-analysis was to assess whether patients with refractory cardiogenic shock treated with IMPELLA in addition to VA-ECMO (ECMELLA) versus ECMO alone may benefit a reduction in early mortality and to assess whether this strategy may result in an increased rate of complications. Methods For this systematic review and meta-analysis, from Dec 2021 to Jan 2022, we searched Scopus, MEDLINE (with PubMed interface) and the Cochrane Central Register of Controlled Trials for randomised controlled trials and observational studies published in any language comparing the use of ECMELLA versus ECMO alone in patients with acute refractory CS (with or without cardiac arrest). Two independent investigators screened titles and abstracts for eligibility, extracted the data, and assessed risk of bias. Risk ratios (RRs) and 95% CIs were calculated with random-effects or fixed-effect models according to the estimated heterogeneity among studies assessed by the I2 index. Primary efficacy endpoint was trial-defined early mortality (in hospital or 30-day mortality). Safety endpoints were major bleeding, the need for renal replacement therapy, hemolysis, severe infections/sepsis and limb ischemia. This study is registered with PROSPERO (CRD42022292517). Results 2061 potentially relevant articles were screened. Our analysis included six retrospective studies with data for 1457 patients. Compared with ECMO alone, ECMELLA was associated with a non-significant reduction in early mortality (RR 0.87, 95% CI 0.72–1.06, p=0.17; Figure 1) and in a significant increase of major bleeding (RR 1.45, 95% CI 1.10–1.91, p=0.009), need for renal replacement therapy (RR 1.70, 95% CI 1.16–2.48, p=0.0008), hemolysis (RR 2.22, 95% CI 1.39–3.56, p=0.005) and limb ischemia (RR 1.61, 95% CI 1.20–2.16, p=0.001). No significant differences were observed in the incidence of severe infections/sepsis between the two groups (RR 1.23, 95% CI 0.97–1.58, p=0.09). (Figure 2) Conclusions The results of this meta-analysis showed that ECMELLA compared to ECMO alone did not significantly reduce early mortality and that, conversely, it resulted in a significantly increased risk of several complication (major bleeding, hemolysis, limb ischemia and renal replacement therapy). This study highlights that, if the benefit of left ventricle unloading with Impella during ECMO in CS shock is uncertain and probably limited to only selected patients, it surely increases the risk of some complications, therefore caution is needed in choosing such a strategy. Funding Acknowledgement Type of funding sources: None.

Background There is limited literature available on the impact of myocardial ischemia but no obstructive coronary arteries (INOCA) on patients' lives. Purpose We sought to determine how INOCA impacts the physical, social, and mental health of persons with this diagnosis. Methods A survey was made available to all members of the patient support group from INOCA International over a 3-month time period. Fitness was estimated using the Duke Activity Status Index (DASI), assessing levels of activities performed prior to the onset of INOCA symptoms, and after the diagnosis of INOCA. The formula to estimate fitness in metabolic equivalents (METs) = 0.43 × DASI + 9.6 / 3.5 Results A total of 297 patients with INOCA responded to the survey; 91.2% were women. The most common diagnosis was coronary microvascular dysfunction (64.3%) and coronary artery spasm (50.5%) (Table 1). 34.4% reported living with symptoms for ≥3 years before their diagnosis of INOCA was made. 77.8% who had been told their symptoms were not cardiac. The symptoms the respondents experienced were numerous, but 92.9% reported symptoms of chest pain, pressure, or discomfort. Fitness levels prior to the onset of INOCA symptoms were significantly higher compared to after diagnosed with INOCA (8.6±1.8 METs vs 5.6±1.8 METs; P Conclusions Living with INOCA has significant impact on physical, mental and social health. Significant physical fitness declines are seen in those living with INOCA and are lower in those experiencing any adverse impact of living with INOCA. Additionally, the impact of INOCA on the ability to work has important economic consequences to both the patient and society. Increased recognition of the impact of INOCA on these aspects of health need to be recognized and further work is needed to better diagnosis and treat the symptoms of INOCA to improve the quality of life, cardiovascular outcomes, and overall health of this frequently encountered cardiovascular disorder. Funding Acknowledgement Type of funding sources: None.

Background Takotsubo syndrome (TTS) is associated with a non-negligible risk of in-hospital (IH) complications. Elevated left ventricular filling pressures (LVFP), measured invasively as LV end-diastolic pressure (LVEDP), showed to predict adverse IH outcomes in this population. Recently, novel indexes of left atrial (LA) function, including LA reservoir and LA pump strain, demonstrated a close correlation with increased LVFP in unselected patients. Purpose To assess the ability of LA reservoir and LA pump strain to improve non-invasive estimation of LVFP and to predict IH complications in TTS patients. Methods We retrospectively enrolled patients with confirmed TTS diagnosis at invasive left heart catheterization and coronary angiography. LVEDP was assessed invasively at the time of catheterization. Transthoracic echocardiography was performed with 48 hours from hospital admission. IH complications were collected, including occurrence of acute heart failure (pulmonary oedema/cardiogenic shock; Killip class III/IV), death from any cause and life-threatening arrhythmias. Results A total of 62 patients were analysed (72.2±10.1 years, female 80%). IH 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 P≤0.001). At multivariate analysis, EF and LVEDP were independent predictors of worse IH outcomes (P≤0.001 and P=0.004 respectively). Correlation analysis proved that lower values of both LA reservoir and pump strain were associated with increasingly higher LVEDP (r −0.859, P≤0.001 and r −0.848, P≤0.001 respectively). Receiving operating characteristic (ROC) curve analysis showed that the AUC for LVEDP to predict IH complications was 0.814 (95% CI 0.679–0.949, P≤0.001) with an optimal cut-off value of 24.5 mmHg (sensitivity 77%, specificity 53%). Therefore, we performed ROC curve analysis to compare the ability of LA strain values and standard echocardiographic parameters currently used for non-invasive LVFP assessment to predict LVEDP ≥24.5 mmHg. As a result, we obtained higher AUC for LA reservoir and pump strain [0.909 (95% CI 0.818–0.999, P≤0.001) and 0.889 (95% CI 0.789–0.988, P≤0.001), respectively] vs E/e' 0.800 (95% CI 0.663–0.937, P≤0.001), LAVi 0.666 (P=0.092) and tricuspid regurgitation (TR) peak velocity 0.582 (P=0.596). 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 (changes in χ2=11.99; 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 IH complications. Funding Acknowledgement Type of funding sources: None.

Background Coronary vasomotor abnormalities are an important cause of myocardial ischemia in patients with non-obstructive coronary artery disease (NOCAD). However, the role of air pollution in determining vasomotor disorders has never been investigated. Purpose In this study, we evaluated the association between long-term exposure to particulate matter (PM) PM2.5 and PM10 and coronary vasomotor disorders in NOCAD patients. Methods Patients with myocardial ischemia and NOCAD undergoing intracoronary provocative test with acetylcholine (ACh) were prospectively enrolled. The test was considered positive for epicardial coronary spasm in the presence of focal or diffuse epicardial coronary diameter reduction ≥90% in comparison with the relaxed state following intracoronary nitroglycerin administration given to relieve the spasm, associated with the reproduction of the patient's symptoms and ischaemic ECG shifts. 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. Only patients with >2 years of available data on air pollution exposure prior to coronary angiography were included. Results We enrolled 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 provocative test. Exposure to PM2.5 (Figure 1) and PM10 was higher in patients with a positive provocative test (p Conclusions We provide novel insights into the missing link between air pollution and ischemic heart disease. In particular, higher exposure to air pollution in patients with myocardial ischemia and NOCAD is associated with coronary vasomotor abnormalities, and PM2.5 is an independent risk factor for the occurrence of epicardial spasm and for MINOCA as clinical presentation. Funding Acknowledgement Type of funding sources: None.

Background Preclinical predictors of worsening heart failure can be monitored by implanted devices and may support the management of patients with heart failure. However, clinical results of such an approach are controversial. Purpose We aimed to assess if guided heart failure management according to device-based remote monitoring strategies is more effective than standard therapy. Methods A comprehensive literature research for randomized controlled trials (RCTs) comparing a strategy of guided heart failure management versus standard therapy was performed on PubMed, Embase, and CENTRAL databases. Incidence rate ratios (IRRs) and associated 95% confidence intervals (CIs) were calculated using the Poisson regression model with random study effects. The primary outcome was a composite of all-cause death and hospitalizations for heart failure. Secondary endpoints included the individual components of the primary outcome. Results A total of 9216 patients from 14 RCTs were included. The average follow-up duration was of 16 months. Compared with standard therapy, guided heart failure management reduced the risk of the composite of all-cause death and hospitalizations for heart failure (IRR 0.86, 95% CI 0.79–0.94, p Conclusion Device-based remote monitoring systems as a tool to guide the management of patients with heart failure were associated with a valuable reduction in the risks of death, hospitalizations for heart failure, and the composite of both, supporting their routine use in clinical practice. Funding Acknowledgement Type of funding sources: None.

Funding Acknowledgements Type of funding sources: None. Background/Introduction Recently, the transcatheter aortic valve replacement (TAVR) has reformed the management of Aortic Stenosis (AS), providing a valid therapeutic alternative to surgical aortic valve replacement (SAVR). Although optimizing the timing of surgery is a crucial aspiration, the introduction of innovative pharmacological therapies able to modify disease evolution might help clinicians to treat patients in a non-invasive way. Several evidences pointed out the role of inflammation, oxidative stress, and pathological remodelling in AS natural history. Purpose The aim of this study is to assess biological pathways modifications after aortic valve replacement, comparing the transcatheter and the surgical approach. Methods We enrolled a total of 35 consecutive patients with severe symptomatic aortic stenosis undergoing aortic valve replacement with transcatheter (n = 19) or surgical (n = 16) approach. Biological samples were collected and stored before (T0) and 72 hours after the procedure (T1). We firstly performed gene expression arrays for a total of 132 genes, on two groups of pooled cDNA from peripheral blood mononuclear cells of TAVR (n = 10) and SAVR (n = 10) patients. Then, taking into account the most relevant result of the arrays, we selected 15 genes for validation. Results Our preliminary data showed several differences in the gene expression levels of the two groups under examination for a large number of molecules, mostly associated with the oxidative balance. More in detail, after procedure, TAVR patients showed higher levels of glutathione peroxidase 1 (GPX1, TAVR p = 0.029; SAVR p = 0.031) and glutathione reductase (GSR, p = 0.029), while SAVR patients showed higher expression of GPX1, catalase (CAT, p = 0.019) and NADPH oxidase 2 (NOX2, p = 0.008), thus confirming an intense post-operative oxidative stress particularly for patients undergoing surgery. Moreover, Caspase 3 (CASP3, p = 0.013), involved in apoptotic pathway and myocyte enhancer factor 2C (MEF2C, p = 0.036), implicated in overload induced hypertrophy genes showed a significantly reduction in their expression after TAVR. Conclusions In our study, we describe different gene expression signatures in patients with an AS diagnosis and their recalibration after AV replacement with two kinds of procedure, TAVR and SAVR. Our data describe for the first time an altered oxidative balance in patient undergoing aortic valve replacement, that is particularly evident for patients undergoing SAVR. A clearer understanding of biological processes taking place in the first hours post AV replacement lays the ground to a more efficient management of post-operative status and, in the incessant research for a tailored therapy, the results of our study add a little piece of information to assist clinicians in selecting the optimal procedure for each patient.

Funding Acknowledgements Type of funding sources: None. Background Coronary microvascular dysfunction (CMD) occurs before left ventricular hypertrophy (LVH) in Anderson Fabry Disease (AFD). Few data exist about the role of CMD in Fabry cardiomyopathy, when overt LVH has already established. Purpose Aim of our study was to assess the relationship between CMD and clinical and echocardiographic features in a cohort of Fabry cardiomyopathy patients. Methods We performed coronary CT scan to exclude epicardial coronary artery disease (CAD) in 27 AFD cardiomyopathy patients with angina and/or evidence of silent ischemia at treadmill stress test. All consenting patients with no CAD (n = 17) were submitted to resting and stress 13N-Ammonia myocardial perfusion PET/CT to assess the presence of CMD. All patients also underwent complete echocardiography. Patients were followed-up for 17.3 ± 12.5 months. Results Global coronary flow reserve (CFR) resulted Conclusions In Fabry cardiomyopathy patients with angina and/or evidence of silent ischemia, the prevalence of CMD is high and it is associated to a more severe cardiac phenotype, including cardiac biomarker and functional capacity. We are not able to draw any conclusion on the possible prognostic role of CMD in Fabry cardiomyopathy.

Background Takotsubo syndrome (TTS) is an acute and reversible form of myocardial injury often preceded by an emotional or physical stressful event. Of importance, TTS may be associated to serious adverse in-hospital complications. Coronary angiography and left ventricle angiography remain a cornerstone for TTS diagnosis. However, the prognostic role of invasively assessed left ventricular end-diastolic pressure (LVEDP) at the time of cardiac catheterization has never been investigated. Purpose We evaluated the role of invasively assessed LVEDP for predicting in-hospital complications in TTS patients compared to the most widely used echocardiographic parameters of ventricular function. Methods We prospectively enrolled 130 patients (mean age 71.2±11.3 years, 114 [87.7%] female) with TTS. Invasive measurement of LVEDP was performed at the time of cardiac catheterization. The rate of in-hospital complications (composite of acute heart failure, cardiogenic shock, life-threatening arrhythmias and all-cause death) was examined. Results In-hospital complications occurred in 37 (28.5%) patients. Patients who experienced in-hospital complications had a higher prevalence of neurological trigger and lower prevalence of emotional trigger, higher LVEDP and mean E/e' ratio and lower LV ejection fraction (LVEF) values compared to those who did not experience in-hospital complications. At multivariable Cox regression, higher LVEDP (hazard ratio [HR] 1.12, 95% confidence interval [CI] [1.05–1.20], p Conclusions LVEDP measured at the time of cardiac catheterization may help in identifying TTS patients at higher risk of cardiovascular events during the hospitalization with relevant therapeutic implications. Of note, in the prediction of in-hospital events the LEVDP performed better than non-invasive indexes commonly used for the assessment of diastolic function. Funding Acknowledgement Type of funding sources: None.

Background/Introduction Acute stress-induced cardiomyopathy, also known as Takotsubo Syndrome (TTS), was originally classified as a benign disease. Nowadays, this assumption has changed, especially in its long-term outcome, due to TTS clinical presentation, that often mirrors the acute myocardial infarction (MI) phenotype. Current knowledge already delineate clinical features distinctive of TTS and MI patients, however, diagnosis requires multiple, expansive, and invasive medical examinations. Moreover, concerning the biological panorama, very slight is known and the lack of a tailored therapy is resented. Therefore, a biological profile for this clinical category could provide easier and less invasive diagnostic tools, leading edge towards novel therapeutic pathways. Purpose The aim of the study is to perform a biological profile of the TTS group compared to the ST Segment Elevation Myocardial Infarction (STEMI) in order to explore the molecular peculiarities attendant the pathophysiologic mechanisms. Methods We performed a gene expression array on two groups of pooled cDNA from peripheral blood mononuclear cells, from TTS (n=11) and STEMI (n=19) patients. We conducted gene expression validations for each enrolled patient through qPCR. Results Our preliminary data displayed several differences in gene expression levels of a grand number of cell adhesion signaling molecule between the two groups. As shown in figure 1, three gene were more expressed in TTS group: Nitric Oxide Synthase 3, also known as endothelial NOS (NOS3; p=0.002), Superoxide dismutase 1 (SOD1; p=0.03) and transferrin receptor (TFRC; p=0.005). Meanwhile, five gene displayed a higher expression in STEMI patients compared to TTS: phospholipase A2 Group 7 (PLA2G7; p=0.04), Galectin 8 (LGALS8; p=0.02), Intercellular Adhesion Molecule 1 (ICAM1; p=0.002), Hyaluronidase 2 (HYAL2; p=0.01) and Hyaluronan Receptor (CD44; p=0.0002). Conclusions The earliest results of this study led us to focus on fewer genes related to endothelial and oxidative stress pathways. TTS is habitually triggered by intense emotional or physical stress. Indeed, our results showed how TTS patients present higher expression of NOS3, SOD1 and TFRC, all components involved in the oxidative stress pathways. In STEMI patients, top expressed genes, such as HYAL2, CD44 and ICAM1, are all associated with extracellular matrix turnover, likely due to the presence of a stenotic plaque and the consequent endothelial derangement. The uncovering of diagnostic biomarkers in TTS might improve the early, non-invasive, stratification of this group of patients, thus facilitating novel and personalized therapeutics design. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The present study was supported by the Italian National Project Grant PRIN 2017.

Introduction Arterial thrombosis underlies most acute CV events. Variants of the Junctional cadherin 5 associated (JCAD) locus were consistently shown to associate with increased risk of acute coronary syndrome. Being a component of cell junctions, JCAD protein is highly expressed in endothelial cells and was shown to promote atherosclerosis by acting on the Hippo pathway through LATS2 kinase. Purpose This project investigated the effect of JCAD in arterial thrombosis by using an established in vivo mouse model of carotid injury. The translational value of animal findings was assessed in primary human aortic endothelial cells (HAECs) as well as in CV patients. Methods JCAD knock-out (Jcad−/−) mice were exposed to photochemically-induced carotid artery endothelial injury to trigger thrombosis. Primary HAECs treated with JCAD small-interfering RNA (si-JCAD), LATS2-silencing RNA (si-LATS2) or control siRNA (si-SCR) were employed for in vitro assays. Plasma JCAD was measured in patients with chronic coronary syndrome (CCS) or ST-elevation myocardial infarction (STEMI). Results Compared to wild-type, Jcad−/− mice displayed reduced thrombus formation as underlined by delayed time to occlusion following endothelial-specific carotid damage. Suggesting a blunted activation of the extrinsic coagulation cascade, Jcad−/− animals showed reduced tissue factor (TF) protein expression and activity in carotid artery lysates (Fig. 1). Increased thrombus embolization episodes and D-dimer further suggested an increased activation of the fibrinolytic system in Jcad−/− mice. Indeed, Jcad−/− mice displayed reduced vascular expression of the fibrinolysis inhibitor plasminogen activator inhibitor (PAI)-1. In contrast, platelets aggregation in response to collagen and thrombin was similar in Jcad−/− and Jcad+/+ mice (Fig. 1). In line with the in vivo data, JCAD-silencing of HAECs inhibited TF and PAI-1 gene and protein expression. In accordance with previous literature, JCAD-silenced HAECs displayed increased levels of LATS2 Kinase, which blunts the Hippo pathway by increasing YAP phosphorylation. Yet, double JCAD and LATS2 silencing did not retrieve the phenotype of control HAECs. Of interest, si-JCAD HAECs showed increased levels of Akt phosphorylation, known to downregulate procoagulant expression and to directly phosphorylate YAP. Treatment with the Akt inhibitor Wortmannin prevented the effect of JCAD silencing on TF and PAI-1 indicating a causative role for this pathway (Fig. 2). Recapitulating in vitro findings, p-Akt and p-YAP levels were higher in arterial tissue of Jcad−/− animals as compared to WT (Fig. 1). Patients with STEMI showed significantly higher plasma levels of JCAD as compared to CCS (Fig. 2). Conclusions JCAD promotes arterial thrombosis by selectively modulating coagulation and fibrinolysis, but not platelet aggregation through endothelial TF and PAI-1. Our findings support the importance of JCAD as a novel therapeutic target for CV prevention. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation

Background Coronary provocative test with acetylcholine (ACh) is of utmost importance and increasingly used in patients with myocardial ischemia and non-obstructive coronary arteries. However, data on safety, predictors and prognostic role of complications during intracoronary provocative testing are scarce. Purpose We assessed the safety of ACh provocative test in patients with myocardial ischemia and non-obstructive coronary arteries. Moreover, we evaluated the predictors and the prognostic implications of complications occurring during the provocative test. Methods We prospectively enrolled consecutive patients undergoing intracoronary ACh provocative test for suspected myocardial ischaemia with angiographic evidence of non-obstructive coronary arteries. Complications during the ACh test were collected. Occurrence of major adverse cardiac events (MACE), arrhythmic events at 24-hours ECG dynamic Holter monitoring and angina status were assessed at follow-up. Results We enrolled 310 patients (mean age 60.6±11.9; 169 [54.5%] chronic coronary syndromes [CCS] and 141 [45.5%] with myocardial infarction and non-obstructive coronary arteries [MINOCA]). The overall incidence of complications was low (9%) with a similar incidence in MINOCA and CCS (10 [7.1%] vs 18 [10.7%], p=0.276, respectively). At multivariate logistic regression analysis, a previous history of paroxysmal atrial fibrillation (Odds Ratio [OR] 12.324, Confidence Interval [CI] 95% [4.641; 32.722], p=0.015) and moderate/severe diastolic dysfunction (OR 3.827, CI95% [1.296; 11.304], p=0.015) were independent predictors for occurrence of complications. The occurrence of complications was not associated with a worse clinical outcome at follow-up (median follow-up 22 months) in terms of both MACE, arrhythmic events and angina burden. Conclusion Intracoronary provocative testing with ACh test is safe in patients with myocardial ischemia and non-obstructive coronary arteries, without differences between MINOCA and CCS. History of paroxysmal atrial fibrillation and moderate/severe diastolic dysfunction predicted the occurrence of complications during ACh test. Of importance, our data can reassure clinicians, as the occurrence of complications did not portend a worse prognosis at follow-up in terms of MACE, arrhythmic events and angina burden. Funding Acknowledgement Type of funding sources: None. Complications and clinical presentationClinical outcome at follow-up

Background The use of low dose of direct oral anticoagulants (DOAC) in adjunct to antiplatelet therapy, known as dual pathway inhibition (DPI), has been tested as an antithrombotic treatment regimen for the prevention of ischemic events in patients with cardiovascular disease (CVD). Purpose The aim of this systematic review and meta-analysis is to determine the overall safety and efficacy of a DPI strategy in patients with CVD. Methods Randomized controlled trials (RCTs) comparing the use of a DOAC at a low dose (LD) regimen, defined as a dosage below that approved for stroke prevention, versus placebo among patients with CVD treated with single or dual antiplatelet therapy were included. Incidence Rate Ratios (IRRs) with 95% confidence Intervals (CIs) were used to overcome different follow-up durations among the included trials. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was major bleeding. A pre- specified subgroup analysis was performed according to the different low dose DOAC regimens used in the DPI arm [LD versus very low dose (VLD)]. Number needed to treat (NNT) and number needed to harm (NNH) were also calculated. Results A total of 55,782 patients from 7 RCTs were included. Compared with placebo, a DPI strategy was associated with a significant reduction in MACE (IRR 0.85, 95% CI 0.78–0.91; NNT 86) and a significant increase of major bleeding (IRR 2.05, 95% CI 1.50–2.80; NNH 89). Moreover, there was a significant reduction of myocardial infarction (IRR 0.86, 95% CI 0.78–0.97; NNT 355) and a significant increase of all bleeding (IRR 1.82, 95% CI 1.49–2.22; NNH 23) with DPI compared to placebo. There were no differences between groups for the outcomes of CV death (IRR 0.90, 95% CI 0.79–1.03; NNT 784), intracranial hemorrhage (IRR 1.18, 95% CI 0.71–1.96; NNH 1810) and fatal bleeding (IRR 1.13, 95% CI 0.76–1.69; NNH 3170). There was a borderline non-significant reduction of all-cause death (IRR 0.92, 95% CI 0.80- 1.01; NNT 821), and stroke (IRR 0.73, 95% CI 0.53–1.01; NNT 315) favouring DPI (Figures 1 and 2). At subgroup analyses a DPI strategy with the use of VLD dose of DOAC (i.e. rivaroxaban 2.5 mg twice daily) mitigated the risk of bleeding without any trade-off in efficacy compared to LD of DOAC regimens and a meta-regression analysis showed a significant interaction between dual antiplatelet therapy use and the risk of major bleeding, intracranial hemorrhage and stroke. Conclusions In patients with CVD, the use of a LD of a DOAC in combination with antiplatelet therapy as part of a DPI regimen is effective in reducing ischemic events, at the expense of increased major and all bleeding but no increase of intracranial hemorrhage and fatal bleeding. A DPI strategy can be particularly advantageous with the use of a VLD of DOAC (i.e. rivaroxaban 2.5 mg twice daily) combined with a single antiplatelet agent among patients at high ischemic and low bleeding risk. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): D.C. declares that he has received consulting and speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, outside the present work. F.C declares that he has received consulting and speaker fees from Biotronic, Amgen, Astra Zeneca, Servier, Menarini, BMS, outside the present work. F.A. declares that she has received consulting and speaker fees from Amgen, Bayer, BMS-Pfizer and Daiichi Sankyo, outside the present work. D.J.A. declares that he has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company and has received payments for participation in review activities from CeloNova and St Jude Medical, outside the present work. D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions and Scott R. MacKenzie Foundation. The remaining authors report no disclosures. Figure 1Figure 2

Background Air pollution is an emerging key player in determining the residual risk of coronary events. However, pathophysiological mechanisms linking air pollution and coronary events have been not adequately investigated. Purpose We assessed the relationship between exposure to air pollutants and mechanisms of coronary instability evaluated by optical coherence tomography (OCT) in patients with acute coronary syndrome (ACS). Methods ACS patients undergoing OCT imaging were retrospectively selected. Mechanism of culprit lesion instability was classified as plaque rupture (PR) or intact fibrous cap (IFC) by OCT, and the presence of macrophage infiltrates (MØI) and thin-cap fibroatheroma (TCFA) at the culprit site was also assessed. Based on each case's home address, exposure to several pollutants was evaluated, including particulate matter 2.5 (PM2.5), particulate matter 10 (PM10), and carbon monoxide (CO). Only patients with >2 years of available data on air pollution exposure prior to ACS were enrolled. Results We included 136 patients [median age 67.0 years (56.2–76.0), 104 (76.5%) male]. Sixty-six patients (48.5%) had PR as mechanism of plaque instability. Patients with PR were exposed to significantly higher PM2.5 levels compared to IFC, and PM2.5 was an independent predictor for PR (OR=1.133, 95% CI [1.020–1.258], p=0.019). Moreover, exposure to higher levels of PM2.5, PM10 and CO was an independent predictor for the presence of TCFA, while PM2.5 and CO levels predicted the presence of MØI. Interestingly, PM2.5, PM10 and CO levels were positively and significantly correlated with serum levels of C-reactive protein. ROC curves were constructed to assess the ability of PM2.5 to predict the presence of plaque rupture, TCFA or MØI. The AUC for PM2.5 to predict plaque rupture was 0.62 (95% CI: 0.52–0.71, p=0.018), for TCFA was 0.71 (95% CI: 0.61–0.80, p Conclusions We provide novel insights into the missing link between air pollution and increased risk of coronary events. In particular, exposure to higher concentrations of air pollutants is a risk factor for vulnerable plaque features and for plaque rupture as mechanism of coronary instability mediated by systemic and local plaque inflammation. Of importance, the thresholds of air pollutants that predicted the presence of vulnerable plaque features are far lower than commonly accepted safety thresholds used to start preventive measures for public health, suggesting that further efforts are needed in order to reduce the adverse effects on the cardiovascular system. Funding Acknowledgement Type of funding sources: None. Air pollutants exposure and OCT featuresROC curve analysis

Background Despite appropriate revascularization strategies, a significant number of patients with myocardial infarction (MI) develop ischemic heart failure suggesting that breakthrough therapies are yet to be approved in this setting. Methylation of non-histone proteins is emerging as a central regulatory mechanism in health and disease. The methyltransferase SETD7 has shown to methylate and alter the function of a variety of proteins in vitro, however its function in the heart is poorly understood. Purpose In the present study we sought to determine the role of SETD7 in myocardial ischemic injury. Methods Neonatal rat ventricular myocytes (NRVM) were exposed to glucose deprivation (GD) for 15 h, in the presence of the selective SETD7 inhibitor [(R)-PFI-2] or its inactive enantiomer [(S)-PFI-2]. Western blot and real time PCR were employed to investigate the effects of energy stress on SETD7 and the Hippo pathway, while apoptosis and oxidative stress were assessed by Caspase-3 activity assay and mitochondrial swelling. YAP activity was assessed through chromatin immunoprecipitation assay (ChIP), its localization was examined by confocal microscopy while mono-methylation was assessed by immunoblotting. Expression of YAP-dependent antioxidant genes was assessed by western blot. SETD7 knockout (SETD7−/−) mice and wild-type (WT) littermates underwent ischemia/reperfusion (I/R) injury. Rats underwent permanent ligation of left anterior descending coronary artery (MI). Left ventricular (LV) myocardial samples were collected from mice undergoing I/R injury and patients with ischemic cardiomyopathy (ICM) and treated ex-vivo with (R)-PFI-2. SETD7 and antioxidant genes expression was assessed in peripheral blood mononuclear cells (PBMCs) from patients with ST-elevation MI (STEMI). Results We show that SETD7 is activated upon energy deprivation in cultured NRVMs and methylates the Hippo pathway effector YAP, leading to its cytosolic retention and impaired transcription of antioxidant genes. Pharmacological inhibition of SETD7 by (R)-PFI-2 restored YAP nuclear localization thus preventing mitochondrial reactive oxygen species (mtROS) and apoptosis. SETD7 deletion in mice attenuated I/R injury, mtROS and LV dysfunction by restoring YAP-dependent transcriptional programs. SETD7/YAP dysregulation was also observed in rats with MI and LV specimens from ICM patients. Of note, (R)-PFI-2 treatment prevented titin oxidation and myofilament stiffness in cardiomyocytes isolated from I/R mice and patients with ICM. Finally, SETD7 was upregulated in STEMI patients and its expression negatively correlated with antioxidant genes. Conclusions Targeting SETD7 may represent a valid therapeutic strategy to protect the heart during ischemia. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Zurich

Funding Acknowledgements Type of funding sources: None. Background Myocardial bridging (MB) is associated with endothelial dysfunction and may represent a cause of angina in patients with non-obstructive coronary artery disease (NOCAD). Purpose Herein, we assessed the interplay between MB and coronary vasomotor disorders, evaluating also their prognostic relevance in patients with myocardial infarction and non-obstructive coronary arteries (MINOCA) or stable NOCAD. Methods We prospectively enrolled consecutive NOCAD patients undergoing intracoronary acetylcholine provocative test to assess the presence of epicardial or microvascular spasm in patients with suspected angina or MINOCA. Myocardial bridging was diagnosed by coronary angiography. The incidence of major adverse cardiac events (MACE), defined as the composite of cardiac death, non-fatal MI and rehospitalisation for unstable angina, was assessed at follow-up. We also assessed angina status using Seattle Angina Questionnaires (SAQ). Results We enrolled 310 patients (mean age 60.6 ± 11.9; 136 [43.9%] men; 169 [54.5%] stable NOCAD and 141 [45.5%] MINOCA). MB was found in 53 (17.1%) patients. MB was an independent predictor of spasm and MINOCA (p Conclusion Among patients with NOCAD coronary spasm associated with MB predicts a worse clinical presentation with MINOCA and a worse clinical outcome at medium-long term follow-up, thus identifying a high-risk subset of patients with MB with relevant therapeutic implications. MB and clinical outcomesCharacteristicsOverall population(n= 310)Presence of Myocardial bridging(n= 53)Absence of Myocardial bridging(n = 257)p valueMACE [n, (%)]25 (8.1)12 (22.6)13 (5.1)

Ventricular septal defect (VSD) is an uncommon but frequently fatal complication following acute myocardial infarction. In medically treated patients, mortality rates exceed 90%, while the surgical repair is associated with better outcomes, even though optimal surgical timing is still under debate.We present the case of a 78-years-old man with no previous remarkable cardiological history admitted to our Emergency Department with the diagnosis of anterior ST-elevation myocardial infarction and significant reduction of left ventricular ejection fraction. The emergency coronary angiography showed sub-occlusion of the left anterior descending coronary artery, treated with stent implantation. The post-procedural echocardiography unveiled the presence of an apical VSD with a large left-to-right shunt, significant right ventricular overload and dysfunction. An intra-aortic balloon pump (IABP) was positioned and, after Heart Team evaluation, a delayed surgical approach was planned. As a bridge to the intervention Levosimendan infusion was administered, on top of IABP support, and a significant improvement in bi-ventricular function and pressure profiles was obtained. Cardiac surgery was successfully performed 9 days after the admission without periprocedural complications.This unique case supports the use of Levosimendan as a valid pharmacological strategy for perioperative management of VSD.

Funding Acknowledgements Type of funding sources: None. Background High-flow nasal cannulae oxygen therapy (HFNCOT) represents a better tolerated alternative to non-invasive pressure support ventilation (NIPSV) for acute cardiogenic pulmonary edema (ACPE) treatment. However, there are still few data on the effect of HFNCOT on cardiac function and hemodynamic. Purpose To assess and compare the effects of NIPSV and HFNCOT in ACPE setting on right ventricular (RV) systolic function and on indices of cardiac filling and output, as measured by echocardiography. Methods This is a cross-over controlled study, enrolling 15 consecutive patients admitted to our Cardiovascular Intensive Care Unit for ACPE and hypoxaemic, normo/hypocapnic acute respiratory failure, with P/F ratio < 200. Each patient received NIPSV, followed by HFNCOT. Full echocardiographic assessment and blood gas analysis (BGA) were performed 40 minutes from onset of each ventilation modality, respectively before NIPSV to HFNCOT switch and before HFNCOT interruption. In particular, RV function parameters, together with RV and atrial strain, were prospectively collected. Results In spite of not significant changes in BGA, RV function was significantly improved under HFNCOT, as compared to NIPSV, as assessed by the following parameters: tricuspid annular plane excursion (TAPSE) (P = 0.001), RV S’ wave (P = 0.007), RV fractional area change (RVFAC) (P = 0.006). Strain analysis confirmed the significant improvement in RV function, with free wall global longitudinal strain (GLS) and free wall and septum GLS significantly higher under HFNCOT, as compared to NIPSV (-21% vs -18% P Conclusions NIPSV significantly affect RV function making more complex the management of patients presenting with ACPE. In this setting, HFNCOT represents a valuable alternative, providing similar respiratory outcomes while preserving good right ventricle performance.

Background Coronary microvascular obstruction (MVO) is a noxious condition frequently occurring in patients with ST-elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI). However, multiple mechanisms are involved in the pathogenesis of MVO and not yet fully understood. Recent studies suggested that perilipin 2 (PLIN2) may play an important role in lipid metabolism of macrophages resident in atherosclerotic plaques along with a role in enhancing oxidative stress. Purpose To study the association between PLIN2 and MVO in STEMI patients undergoing primary PCI. We also assessed the role of PLIN2 to predict future major cardiovascular events (MACEs). Methods STEMI patients undergoing primary PCI were enrolled. PLIN2 was dosed within 24 hours from admission in peripheral blood monocytes. MVO was assessed using TIMI flow grade and myocardial blush grade on coronary angiogram after PCI, and patients were stratified accordingly (MVO or noMVO). Major adverse cardiac events (defined as a composite of cardiac death, non-fatal myocardial infarction, re-admission for heart failure and target vessel revascularization) were assessed at clinical follow-up. Results Among 100 STEMI patients (mean age, 65.2±12.0 years, 81 males), 33 (33.0%) had MVO. Patients with MVO were older, had higher troponin I peak, C-reactive protein and lower left ventricular ejection fraction on admission. Patients with MVO had significantly higher levels of PLIN2 (1.03±0.28 vs. 0.90±0.16, p=0.019) compared to noMVO patients. Age [OR (95% CI) per year, 1.045 (1.005–1.087), p=0.026] and PLIN2 [OR (95% CI) per unit, 16.606 (2.027–136.030), p=0.009] were associated with MVO at univariate logistic regression analysis. However, only PLIN2 levels [OR (95% CI) per unit, 12.325 (1.446–105.039), p=0.033] were independently associated with MVO at multivariate analysis. Follow up data were available for 76 patients (76%). After a mean follow up of 182.2±126.6 days, 13 MACEs occurred. Patients with MVO had more MACEs [9 (37.5%) vs. 4 (7.7%), p Conclusions In STEMI patients undergoing primary PCI, PLIN2 was independently associated with MVO. PLIN2 was an independent predictor of MACEs at clinical follow-up. These findings suggest that PLIN2 may represent a promising therapeutic target, opening the avenue towards novel therapeutic approaches for MVO. Funding Acknowledgement Type of funding source: None

Background The use of Optical Coherence Tomography (OCT) in acute coronary syndromes (ACS) allows recognizing ruptured fibrous cap (RFC) and intact fibrous cap (IFC) culprit lesions. The biological differences between them, as recently pointed out in translation studies, highlight different mechanisms for a similar clinical manifestation that might deserve different therapeutic approaches. The relationship between endothelial wall shear stress (WSS) and ACS has been demonstrated, however the differences in WSS features between RFC and IFC have not been elucidated. Purpose The aim of this study is to provide a fluid-dynamic and biological description of unstable and stable (SA) plaques, according to OCT analysis. Methods We enrolled 10 SA and 20 Non-ST Elevation Myocardial Infarction (NSTEMI)-ACS patients, with IFC (n=10) and RFC (n=10) culprit lesions according to OCT analysis. We performed Real-time PCR primer array on pooled Peripheral Blood Mononuclear Cell (PBMC) for 30 different molecules whose expression is strictly dependent on WSS. High-fidelity 3D-coronary artery models were created for 3 patients per group, applying previously validated methodologies. Results Among the groups we found a broad difference in molecular expression (Fig. 1A), with RFC displaying higher levels of molecules involved in vasoconstriction/dilatation (EDN1, NOS3), cellular adhesion (ICAM1), and peptidase inhibition (PI16). A significantly higher WSS was observed in RFC group (p Conclusions Our data demonstrated that IFC and RFC unstable plaques are associated with different WSS conditions, alongside with the expression of different molecular patterns specifically related to altered WSS. In the era of precision medicine these findings may have relevant therapeutical implications. Funding Acknowledgement Type of funding source: None

Background PLATO study showed that Ticagrelor (Ti) significantly reduced the rate of death from vascular causes, myocardial infarction or stroke without a significant increase of major bleeding vs Clopidogrel (Cl). Previous studies demonstrated the stronger direct anti-platelet effect of Ti versus Cl. Few data exist about the indirect anti-platelet properties and pleiotropic effects, eventually involved in the positive effect of Ti on acute coronary syndrome (ACS) outcome. Aim As Ti has multiple pleiotropic effects, we sought to assess whether the different outcome of Ti versus Cl in NSTE-ACS patients could be explained, at least in part, by different modulation of circulating microRNA (miRNA). The primary endpoint was to characterize the effect of the two different P2Y12 inhibitors on miRNA expression. Secondary endpoint was to correlate miRNA profile to clinical outcome. Methods Thirty-one patients with a diagnosis of NSTE-ACS were enrolled in this study. Patients were randomized for Ti or Cl assumption before undergoing PCI. Clinical characteristics were homologues between Ti and Cl groups. Blood samples were drawn at different time point (T0, T1 and T2) to test miRNA modulation and stability (T0, at baseline; T1, three hours after drug administration; T2, twenty-four hours after coronarography). Plasma RNA was extracted and pooled for microarray PCR based panel of ninety miRNA analysis. MiRNA expression was normalized on the global mean of each patient. Levels of circulating miRNAs were compared using statistical tests, assuming significance at P Results A panel of seven circulating miRNAs associated with atherosclerosis, thrombosis and inflammation were selected for validation (miR-652-3p; miR-26-5p; miR-25-3p; miR-let7c; miR-155-5p; miR-222-3p; miR-223-3p). Microarray analysis showed an opposite modulation of most miRNAs at T0, T1 and T2 in patients with Cl or Ti treatment. In particular, Cl group showed an upregulation of most miRNAs, while Ti administration caused their down-regulation. Of the seven miRNA selected for validation, miR-652-3p, expression at T1 showed a significantly modulation in patients in Cl treatment compared to Ti (T1 Cl 2,637±1,092, T1 Ti 0,660±0,171; p=0.03). MiRNA-652-3p has a validated pro-atherogenic role. On five-years follow, an higher rate (40%) of cardiovascular events (new ACS, recurrent ischemia and stent thrombosis) was reported in the Cl group compare to Ti. Indeed, no one death or bleeding occurred. Conclusion This data suggest that Ti has a protective role down-regulating pro-atherogenic and pro-thrombotic miRNAs (miR-652-3p, miR-let7c, miR-223-3p, miR-155-5p) and promoting the expression of anti-atherogenic miRNAs (miR-25-3p) when compared to Cl. This may contribute to explain the positive effect on clinical outcome of Ti. Although the small number of patients, this pilot study gives another evidence about the multiple positive pleiotropic effect of Ti. Figure 1. miRNA 652-3p expression Funding Acknowledgement Type of funding source: None

Background Brain-derived neurotrophic factor (BDNF) is a neurotrophine that plays a key role in the regulation of both central and peripheral nervous system. Moreover, BDNF is secreted in multiple tissues and exerts systemic, autocrine, and paracrine effects in the cardiovascular system. Of importance, BDNF expression was enhanced in macrophages and smooth muscle cells in atherosclerotic coronary arteries and may be involved in thrombus formation. Thus, BDNF has been suggested as an important link between inflammation and thrombosis, potentially involved in the pathogenesis of acute coronary syndrome (ACS). Purpose In our study we aimed at assessing serum levels of BDNF in patients with ACS, evaluating differences according to clinical presentation [ST-segment elevation myocardial infarction (STEMI) vs. Non-ST-segment elevation ACS (NSTE-ACS)]. Moreover, we assessed the presence of optical coherence (OCT)-defined macrophage infiltrates (MØI) in the culprit vessel of ACS patients and evaluated their relationship with BDNF levels. Methods ACS patients were prospectively selected. Blood samples were collected at admission and serum levels of BDNF were subsequently assessed. Presence of OCT-defined MØI along the culprit vessel was assessed. Results 166 ACS patients were enrolled [mean age 65.3±11.9 years, 125 (75.3%) male, 109 STEMI, 57 NSTE-ACS]. Serum levels of BDNF were higher among STEMI patients compared with NSTE-ACS [median (IQR) 2.48 pg/mL (1.54–3.34) vs. 2.12 pg/mL (1.34–2.47), p=0.007], while C-reactive protein levels did not differ between the two groups. OCT assessment was performed in 53 patients and MØI were detected in 27 patients. Of importance, patients with MØI in the culprit vessel had higher levels of BDNF compared with patients without MØI [median (IQR) 2.23 pg/mL (1.38–2.53) vs. 1.41 pg/mL (0.93–2.07), p=0.023], while C-reactive protein levels did not differ between the two groups. Of note, at multivariate regression analysis BDNF levels were independent predictor of MØI [OR: 2.20; 95% CI (1.02–4.74), p=0.043]. Conclusions Serum levels of BDNF may reliable identify the presence of local macrophage inflammatory infiltrates in patients with ACS. Moreover, BDNF levels are higher in patients with STEMI compared with NSTE-ACS. Taken together, these data suggest that BDNF may represent an interesting link between local inflammatory activation and enhanced thrombosis in ACS. BDNF serum levels Funding Acknowledgement Type of funding source: None

Background Plaque erosion (PE) is responsible for at least one-third of acute coronary syndrome (ACS). Inflammatory activation is considered a key mechanism of plaque instability in patients with plaque rupture through the release of metalloproteinases and the inhibition of collagen synthesis that in turns lead to fibrous cap degradation. However, the clinical relevance of macrophage infiltration has never been investigated in patients with PE. Purpose In our study, we aimed at assessing the presence of optical coherence tomography (OCT)-defined macrophage infiltrates (MØI) at the culprit site in ACS patients with PE, evaluating their clinical and OCT correlates, along with their prognostic value. Methods ACS patients undergoing OCT imaging and presenting PE as culprit lesion were retrospectively selected. Presence of MØI at culprit site and in non-culprit segments along the culprit vessel was assessed. The incidence of major adverse cardiac events (MACEs), defined as the composite of cardiac death, recurrent myocardial infarction and target vessel revascularization (TVR), was assessed [follow-up median (interquartile range, IQR) time 2.5 (2.03–2.58) years]. Results We included 153 patients [median age (IQR) 64 (53–75) years, 99 (64.7%) males]. Fifty-one (33.3%) patients presented PE with MØI and 102 (66.7%) PE without MØI. Patients having PE with MØI compared with PE patients without MØI had more vulnerable plaque features both at culprit site and at non-culprit segments. In particular, culprit lesion analysis demonstrated that patients with PE with MØI had a significantly thinner fibrous cap [median (IQR) 100 (60–120) μm vs. 160 (95–190) μm, p Conclusion Our study demonstrates that among ACS patients with PE the presence of MØI at culprit lesion is associated with a more aggressive phenotype of coronary atherosclerosis with more vulnerable plaque features, along with a worse prognosis at a long-term follow-up. These findings are of the utmost importance in the era of precision medicine because clearly show that macrophage infiltrates may identify patients with a higher cardiovascular risk requiring more aggressive secondary prevention therapies and a closer clinical follow-up. Prognosis Funding Acknowledgement Type of funding source: None

Background The imbalance between protective and harmful bacteria in the microbial communities leads to a non-physiological condition, known as “dysbiosis”. In the last decade, several studies have suggested that gut microbiota can contribute to the development and progression of various disease including cardiovascular disease through metabolism-mediated pathways. The production and the release of bacterial metabolites, including Trimethylamine N-oxide (TMAO), can affect host health acting to distant organs. Purpose The aim of the present study was to explore the gut microbiota and the levels of TMAO in patients with stable angina (SA) and acute coronary syndrome (ACS) with or without elevation of the ST segment, respectively STEMI and NSTEMI, and in control subjects. Methods Feces were obtained from ACS (n=31) and SA (n=23) patients and controls (n=24). Genomic DNA was isolated using the QIamp DNA Stool Mini Kit. Samples were subjected to 16S rRNA gene V3–V4 region sequencing by an Illumina MiSeq TM platform. A combination of software packages QIIME and VSEARCH was used to generate a biological observation matrix (BIOM) at different taxonomic levels (from phylum to genus). The BIOM was analysed using the Web-based program MicrobiomeAnalyst. β-diversity between groups was obtained by weighted UniFrac distance metric analysis. Serum TMAO levels were measured with a UPLC-MS/MS mass spectrometry in SA and ACS patients. Results β-diversity analysis showed a different bacterial composition in SA and ACS patients and controls ([PERMANOVA] F-value: 1.9706; R-squared: 0.050567; p-value Conclusion These results, taken together, suggest that gut microbiota and its derived metabolites might play an essential role in the progression of atherosclerosis and in coronary plaque instability. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Linea D1 Università Cattolica del Sacro Cuore

Background Previous studies have reported a circadian variation in the onset of ST-segment elevation myocardial infarction (STEMI). However, underlying mechanisms for the circadian variation have not been fully elucidated. Purpose We investigated the relationship between onset of STEMI and the underlying pathology using optical coherence tomography (OCT). Methods Patients presenting with STEMI were selected from an international, multi-center, longitudinal registry study, which included patients who underwent OCT imaging of the culprit lesion at 11 institutions in 6 countries. Onset of MI was estimated using the time of OCT imaging. Patients were divided into 4 groups based on the estimated time of onset (00:00–05:59, 06:00–11:59, 12:00–17:59, or 18:00–23:59). Underlying pathologies of MI (plaque rupture, plaque erosion, and calcified plaque) were compared among the 4 groups. Results Among 648 patients, plaque rupture was diagnosed in 386 patients (59.6%), plaque erosion in 197 patients (30.4%), and calcified plaque in 65 patients (10.0%). A marked circadian variation was detected in the incidence of plaque rupture with a peak at 9:00, whereas it was not evident in plaque erosion or calcified plaque. The probability of plaque rupture increased in the periods of 06:00–11:59 (odds ratio: 2.13, 95% confidence interval: 1.30 to 3.49, p=0.002) and 12:00–17:59 (odds ratio: 2.10, 95% confidence interval: 1.23 to 3.58, p=0.005), compared to the period of 00:00–05:59. This circadian pattern was observed only during weekdays (p=0.013) and it was not evident during the weekend (p=0.742). Conclusions Plaque rupture occurred most frequently in the morning and the circadian variation was evident only during the weekdays. Acute MI caused by plaque rupture may be related to catecholamine surge. Funding Acknowledgement Type of funding source: None

Background Several studies suggest that an alteration of monocyte metabolism might be implicated in inflammatory diseases. Enhanced glycolysis might be a hallmark of pro-inflammatory monocyte subsets. Improved glycolysis enables the immune cells to generate sufficient ATP and biosynthetic intermediates to carry out its particular effector functions. For macrophages this includes phagocytosis and inflammatory cytokine production. Pyruvate Kinase isozyme M2 (PKM-2) catalyzes the final step of glycolysis producing pyruvate and ATP. Latest studies have shown that a member of Jumonji family (JMJD8) acts as a positive regulator in TNF-induced NF-kB signaling leading to pro-inflammatory pathways in macrophages and is involved in angiogenesis and cellular metabolism through interacting with PKM-2 in endothelial cells. Purpose The aims of the study are to assess the expression of the glycolytic key enzyme PKM-2 in CD14+ monocytes obtained from patients with non-ST-elevation myocardial infarction (NSTEMI) or with stable angina (SA). Furthermore, the expression of JMJD8 was evaluated. Methods 30 patients with NSTEMI and 30 patients with SA were enrolled. Peripheral blood mononuclear cells were obtained from whole blood samples. For cytoplasmatic protein identification, cells were fixed and permeabilized and then incubated with fluorochrome-conjugated mAbs anti-CD14, anti-PKM-2 and anti-JMJD8. For analysis we used Two-tailed Mann-Whitney non parametric Comparison test. Results CD14+ monocytes from NSTEMI patients showed reduced expression of the key glycolytic enzyme PKM-2 as compared to CD14+ monocytes from SA patients (p=0.02) (Figure 1). JMJD8 expression in NSTEMI patients is increased compared with SA patients (p=0.02) (Figure 2). Conclusion This study introduces a role for immune-metabolism in the immunity dysregulation described in ACS patients and provides novel insights into the mechanisms responsible for coronary instability. Taking their potential interaction into account, our data suggest that in acute setting glycolysis key enzyme PKM2 expression is downregulated. Besides, JMJD8 protein levels increase in NSTEMI patients acting as potential limiting factor of PKM2 function. Moreover, our data propose the potential roles of immune-metabolism to detect novel therapeutic targets, associated with an accurate patient stratification based on immune-metabolic profiles, for prevention and treatment of atherosclerosis, in the perspective of a personalized medicine approach. Funding Acknowledgement Type of funding source: Private hospital(s). Main funding source(s): Fondazione Policlinico A. Gemelli

Background- Identification of variants of uncertain significance (VUSs) poses relevant challenges in counseling and managing patients. They have an unknown impact on health, making the genetic tests clinically irrelevant. Recent studies demonstrate that a routine reclassification analysis enables to reclassify from 20% to 80% of this type of variant, improving risk stratification. Purpose- We investigated whether, in the context of inherited cardiac conditions, a review of the updated literature, including new functional data, allele frequency (GnomAD) and segregation analysis may help in the variant reclassification. Methods- Retrospective review of all VUSs in genes associated with inherited cardiac conditions identified in our cardiogenetic clinic between 2016 and 2018. Results- Thirty-one VUSs, classified using ACMG guidelines, were identified in 26 cases with a confirmed or suspected diagnosis of inherited cardiovascular diseases, including Long QT syndrome, Brugada syndrome, Arrhythmogenic Cardiomyopathy and Hypertrophic Cardiomyopathy). Twentyfour variants were identified in well-defined causative genes (SCN5A, KCNQ1, KCNH2, KCNE1, DSP, DSG2, MYH7, TPM1, TNNI3, TNNT2, CACNA1C, MYL3) while the remaining variants were identified in minor genes with limited evidence to support their disease causation as, ANK2 and AKAP9 gene. Preliminary results of the reclassification analysis showed that two variants were downgraded to likely benign (LB) applying the BS1 criterion (allele frequency) and 4 variants were upgraded to likely pathogenic (LP) according to novel published data and family segregation studies. Moreover, further studies to assess cosegregation in other variants are still ongoing. Conclusion- Based on our experience, 25% of variants of uncertain significance in well-defined causative genes, identified in patients with a confirmed or suspected diagnosis of inherited cardiovascular disease, were reclassified. These findings suggest that re-evaluation of genetic test results should be performed routinely in all diagnostic labs, in order to improve risk stratification and identification of family members at high risk.

Background Patients with severe aortic regurgitation (AR) are treated by surgery and have variable left-ventricular (LV) “reverse remodelling” after intervention. Transcatheter-aortic-valve replacement (TAVR) might be considered in selected AR patients. Purpose To evaluate the hemodynamic and structural impact of TAVR in patients with pure AR. Methods Consecutive AR patients underwent TAVR in our Institution were identified. Left heart catheterization before and after TAVR and complete echocardiographic assessment before TAVR, after (24–72 hours) TAVR and at follow-up (3–12 months) were systematically performed. Hemodynamic and echocardiographic parameters were compared before and after TAVR. Results Twenty-two patients with severe AR, high surgical risk and advanced heart damage were treated by TAVR using mainly self-expandable prostheses. The procedure was successful in 21 patients (95.5%). An immediate hemodynamic impact of the TAVR procedure was documented by different parameters and included significant decrease in LV end-diastolic pressure (from 26.2 to 20.1 mmHg, P=0.012). Significant reduction in LV size (left ventricular end diastolic diameter (LVEDD): 60.0±8.0 mm vs 54.6±8.1 mm, p=0.002) and mass (left ventricular mass indexed (LVMi): 163.2±58.8 g/m2 vs 140.2±45.6 g/m2, p 0.004) as well as a sharp reduction in systolic-pulmonary-arterial-pressure (48.3±17.6 vs 32.9±7.8 mmHg, p Conclusions In patients with severe AR, TAVR determines a profound impact on heart remodelling, which is early detectable and durable. Impact of TAVR in pure AR Funding Acknowledgement Type of funding source: None

A 54-year-old female presented to our Emergency Department with acute pulmonary edema. On physical examination she was tachypneic with arterial oxygen saturation of 91% and a grade 3/6 systolic murmur in the apex and left second intercostal space that was irradiated to the intrascapular area. Bilateral femoral and pedal pulses were quite faint on palpation. The blood pressure was 260/120 mmHg. Results of routine blood chemistry were normal with the exception of increased NT-proBNP (2746 pg/mL). Twelve-lead electrocardiogram revealed left ventricular hypertrophy with repolarization abnormalities and left atrial enlargement. The two dimensional (2D) echocardiography showed significant left ventricular hypertrophy (RWT 0.6; LVmass index 150 g/m2), no wall-motion abnormalities and normal left ventricular ejection fraction (EF 60%) but with reduced longitudinal components at TDI evaluation (6 cm/s). Severe ventricular diastolic dysfunction was detected with E/A 2,11 and E/e" 26 with a significant left atrial dilatation (LAVi 73 ml/m2) and severe pulmonary arterial hypertension ( PASP of 85 mmHg) . We were unable to visualize the aortic arch but reduced/absent pulsatile wall motion of abdominal aorta was identified. The patient reported to be affected by unrepaired aortic coarctation diagnosed at the age of 32 during pregnancy. She refused the surgical treatment twice and the she did not undergo any specific follow up but she had several admissions in emergency department for uncontrolled arterial hypertension. Our further evaluation with CT angiography showed a severe narrowing of the post isthmic aortic lumen with significant development collateral vessels (Figure 1). The patient was discharged after resolution of pulmonary edema and titration of hypertension treatment with a planning of hybrid approach to treat the aortic coarctation. The case shows a restrictive cardiomyopathy with post-capillary pulmonary hypertension due to severe unrepaired aortic coarctation. Abstract P722 Figure. CT angiography,echo, right heart cath

Objective Preliminary studies showed the accuracy of machine learning based automated dynamic quantification of left ventricular (LV) and left atrial (LA) volumes. We aimed to evaluate the feasibility and accuracy of this new Dynamic Heart Model (DHM) software in an unselected population undergoing transthoracic echocardiography (TTE). Methods. We enrolled 91 consecutive unselected patients (80% in sinus rhythm) referred for clinically indicated 2D TTE, who also underwent single 3D TTE image acquisition from the apical 4-chamber view. 2D images were analyzed to measure ejection fraction, LV and LA volumes; 3D images were analyzed using Dynamic Heart Model (DHM) software (Philips Healthcare), which automatically measures chamber volumes throughout the cardiac cycle, resulting in LV and LA volume-time curves. Average time of analysis, feasibility, image quality were recorded and results compared between the 2D and 3D techniques. Results. Quality of the 91 2D TTE images was graded as poor (N = 13), satisfactory (N = 45) and good (N = 33). The use of DHM was feasible in 79/91 cases (87%). The remaining 12 datasets could not be analyzed because of poor images (N = 10) or incorrect automated border detection (N = 2): in these cases, the software did not accurately identify endocardial borders due to LV cavity near obliteration or extreme LA enlargement. When feasible, the boundary position was considered accurate in 61/79 patients (77%), while minor manual correction of the LV/LA borders was needed in the remaining cases. In only 1 case the reconstruction was considered unreliable because it needed major corrections. The overall time required to obtain DHM data was approximately 45 seconds. In all cases in which DHM was used, not only shapes of LV and LA were very well defined, but also functional curves were physiologically plausible. Even in the 13 patients in whom the 2D image was suboptimal, the DHM was not only feasible but also accurate endocardial boundaries in 8 cases, without (N = 5) or with only minimal manual corrections (N = 3). As expected, 3D LV volumes were slightly hige than 2D ones ( EDV 153.9 ± 59.8 vs 121.4 ± 47.3 mL, respectively), while LV EF and LA volumes were similar (EF 58.8 ± 11.8 vs 59 ± 11.8% and LA volume 92 ± 39.3 vs 83.4 ± 32.1 mL, respectively). Conclusions. The new DHM software is quick, feasible and accurate in the majority of unselected patients, including those with suboptimal 2D images or in atrial fibrillation. Introduction of this automated analysis into clinical practice can reduce examination time, while providing reliable information not only on volumes but also on function of the left heart chambers.

Background Ticagrelor is a reversibly binding, direct-acting, oral, P2Y12 antagonist used for the prevention of atherothrombotic events in patients with coronary artery disease (CAD). Ticagrelor blocks adenosine reuptake through the inhibition of equilibrative nucleoside transporter 1 (ENT-1) on erythrocytes and platelets, thereby facilitating adenosine-induced physiological responses such as an increase in coronary blood flow velocity. Meanwhile, adenosine plays an important role in triggering ischemic preconditioning through the activation of the A1 receptor. Therefore, an increase in ticagrelor-enhanced adenosine bioavailability may confer beneficial effects through mechanisms related to preconditioning activation and improvement of coronary microvascular dysfunction. Methods To determine whether ticagrelor can trigger ischemic preconditioning and influence microvascular function, we designed this prospective, open-label, pilot study that enrolled patients with stable multivessel CAD requiring staged, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI). Participants will be randomized in 1:1 ratios either to ticagrelor (loading dose (LD) 180 mg, maintenance dose (MD) 90 mg bid) or to clopidogrel (LD 600 mg, MD 75 mg) from 3 to 1 days before the scheduled PCI. The PCI operators will be blinded to the randomization arm. The primary endpoint is the delta (difference) between ST segment elevations (in millimeters, mm) as assessed by intracoronary electrocardiogram (ECG) during the two-step sequential coronary balloon inflation in the culprit vessel. Secondary endpoints are 1) changes in coronary flow reserve (CFR), index of microvascular resistance (IMR), and FFR measured in the culprit vessel and reference vessel at the end of PCI, and 2) angina score during inflations. This study started in 2018 with the aim of enrolling 100 patients. Based on the rate of negative FFR up to 30% and a drop-out rate up to 10%, we expect to detect an absolute difference of 4 mm among the study arms in the mean change of ST elevation following repeated balloon inflations. All study procedures were reviewed and approved by the Ethical Committee of the Catholic University of Sacred Heart. Discussion Ticagrelor might improve ischemia tolerance and microvascular function compared to clopidogrel, and these effects might translate to better long-term clinical outcomes. Trial registration EudraCT No. 2016–004746-28. No. NCT02701140. Trial status Information provided in this manuscript refers to the definitive version (n. 3.0) of the study protocol, dated 31 October 2017, and includes all protocol amendments. Recruitment started on 18 September 2018 and is currently ongoing. The enrollment is expected to be completed by the end of 2019. Trial sponsor Fondazione Policlinico Universitario A. Gemelli – Roma, Polo di Scienze Cardiovascolari e Toraciche, Largo Agostino Gemelli 8, 00168 Rome, Italy.

Background Right ventricular hypertrophy (RVH) is a common finding in Anderson Fabry disease (AFD). In other infiltrative and storage cardiomyopathies right ventricular (RV) involvement may influence prognostic stratification. Nevertheless, the prognostic implications of right ventricle involvement in AFD have never been assessed. Purpose Evaluation of the prognostic significance of RVH and RV systolic function in AFD cardiomyopathy. Methods Forty-five AFD patients (56% male) with extensive baseline evaluation, including assessment of RVH and RV systolic function, were followed-up for an average of 44.9 ± 8.5 months. RV systolic function was assessed by standard and tissue Doppler echocardiography and quantified using RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE) and Systolic tissue Doppler velocity of the tricuspid annulus (RV Sa). Cardiovascular events were defined as new-onset atrial fibrillation, heart failure or pace-maker implantation; renal events were defined as progression to dialysis and/or renal transplantation or significant worsening of glomerular filtration rate; cerebrovascular events were defined as stroke or transient ischemic attack. The outcome was defined as the time to death or the first event in any of the above predefined categories. Results 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 major events including two deaths. Pace-maker implantation (6 cases) was the most common type of event. At univariate analysis several variables were associated with the occurrence of events, including RVH and indexes of RV systolic function. However, at multivariate analysis only proteinuria (HR:8.3, 95% CI: 2.88 to 23.87, p ˂0.001) and LV mass indexed (HR: 1.01, 95% CI: 1.00 to 1.03, p = 0.03) were independent predictors of outcome. Conclusions The presence and extension of RVH is not associated with outcome in AFD. Our study confirms that at variance with other infiltrative or storage cardiomyopathies, RV involvement in AFD is an innocent bystander and does not influence prognosis.

Additional file 2. SPIRIT 2013 Checklist.

Additional file 1. Details related to main pharmacological interactions and adverse events definition and reporting are provided in the additional file, enclosed in the manuscript.

Background Global longitudinal strain (LS) is a sensitive marker of ischemic myocardial damage and predicts adverse left ventricular (LV) remodeling and outcome, independently of infarct size. In healthy subjects, regional LS increases from LV base to apex and enhances under physical or pharmacological stress, while in ST-elevation myocardial infarction (STEMI), response to dobutamine depends on transmurality of necrosis. It is known that coronary flow reserve during adenosine (ADN) is impaired both in ischemic and remote myocardium, but effect of ADN on strain reserve has never been investigated. Similarly, LS response to ADN in ischemic (iLS) and remote (rLS) myocardium and their relative contribution to LV function and remodeling are still unknown. Methods 61 consecutive patients with first STEMI (26 anterior, 29 inferior, 6 lateral), treated by successful primary percutaneous coronary intervention (PCI) followed by PCI of non-culprit coronary arteries, underwent rest and stress ADN (140 mcg/kg/minutes in 90 seconds) echocardiography at discharge (7 ± 2 days after admission). LV end-diastolic volume indexed for body surface area (EDV), ejection fraction (EF) and wall motion score index (WMSI) were measured at rest, while GLS, iLS and rLS analysis was performed both at rest and during stress. Ischemic and remote myocardium was allocated, by standard LV segmentation, basing on the culprit coronary artery. Results Significant differences existed among anterior, inferior and lateral STEMI in median (iQr) EDV [52 (45-59) vs 45 (36-51) vs 48 (45–56) ml, respectively, p=.034 overall], EF [47 (37-58) vs 58 (53–61) vs 56 (46-60)%, respectively, p=.002 overall], WMSI [1.63 (1.38–2) vs 1.25 (1.19-1.47) vs 1.41 (1.30-1.75), respectively, p=.001 overall]. GLS differed among anterior, inferior and lateral STEMI both at rest [13.75 (11.63-16.1) vs 19.5 (17.15-22.4) vs 17.85 (17.02-19), respectively, p Conclusions In the subacute phase of STEMI, GLS, iLS and rLS are heterogeneous and depend on infarct site. After ADN, there is no strain reserve in ischemic neither in remote myocardium. This may reflect regional differences in the response of microcirculation and myocardium to ischemia or may underlie pre-existing pathophysiological differences in the coronary circulation

Duchenne muscular dystrophy (DMD) is an inherited X-linked recessive neuromuscular disease caused by mutations of the dystrophin gene, leading to early and progressive muscle deterioration and dilated cardiomyopathy. The aim of this investigation was to assess whether treatment with sacubitril/valsartan (S/V) is well tolerated and may have beneficial effects in DMD patients with left ventricle (LV) dysfunction.We administered S/V to 3 DMD patients (19-29 yeard old) with LV ejection fraction35% at echocardiography but no symptoms of heart failure. All patients were on optimal medical therapy. S/V was initiated at a very low dose of 12/13 mg/die, after withdrawal of angiotensin-converting enzyme inhibitor therapy, and slowly titrated to the dose of 49/51 mg twice daily or the maximally tolerated dose. Clinical and echocardiographic follow-up was performed after 3, 6 and 12 months.At baseline, the LV ejection fraction was 32±1%. A significant improvement of LV ejection fraction was observed at 3 months (44.0±6.0%; p0.05), which was maintained at 6 (45.7±5.0%) and 12 (43.3±3.2%) months (p0.05 for both). No relevant side effects were reported throughout the period of the study.Our preliminary data suggest that, in DMD patients with reduced LV ejection fraction, S/V is safe and may improve LV function.

Background Seasonal variations in acute coronary syndrome (ACS) has been known with the winter being the peak in incidence and mortality. However, underlying pathophysiology for this variation has not been studied. Purpose We sought to compare pathobiology of the culprit lesions assessed by optical coherence tomography (OCT) among the four seasons. Methods Patients with ACS who underwent OCT were recruited from 6 countries in the Northern Hemisphere. The prevalence of 3 most common pathologies, plaque rupture, plaque erosion and calcified plaque, and other features of coronary plaques were compared among the four seasons. Results In 1113 patients with ACS, 284 (25%) patients were admitted in spring, 243 (22%) patients in summer, 290 (26%) patients in autumn and 296 (27%) patients in winter. The proportion of underlying 3 pathologies was significantly different in each season (prevalence of plaque rupture, plaque erosion, calcified plaque was 50%, 39%, and 11%, respectively in the spring; 44%, 43%, and 13% in the summer; autumn: 49%, 39%, and 12% in the autumn; 57%, 30%, and 13% in the winter; P=0.039). The proportion of plaque rupture was higher in winter but lower in summer, and that of plaque erosion was higher in summer, but lower in winter. Maximum and minimum temperatures on the day of OCT procedure were significantly lower in the plaque rupture group than in the plaque erosion group (P=0.02 and P=0.012, respectively). In the rupture group, the prevalence of hypertension was significantly higher in winter, but in the erosion group, it was not different among the four seasons. Figure 1. The proportion of culprit lesion characteristics were significantly different among the 4 season groups. (P=0.039) The proportion of plaque rupture was significantly higher in winter but lower in summer. In contrast, the proportion of plaque erosion was higher in summer, but lower in winter. Conclusions Seasonal variation of the underlying mechanisms of ACS reflects different pathobiology. The proportion of plaque rupture is highest in winter and the proportion of plaque erosion is highest in summer. A different approach may be needed for the prevention and treatment of ACS depending on the season of its occurrence.

Background The relation between culprit plaque morphology and the clinical presentation of an acute myocardial infarction (AMI) has not been examined in detail. Purpose To study the culprit plaque morphology in patients with AMI with or without preinfarction angina using optical coherence tomography (OCT) imaging. Methods A total of 102 patients with AMI (32 STEMI, 70 NSTEMI) who underwent OCT imaging before percutaneous coronary intervention were enrolled. Patients were classified as: i) having either intermittent chest pain in the six hours preceding the final episode of pain, or unstable angina (or both) in the week preceding AMI (preinfarction angina group); or ii) having a single episode of chest pain without unstable symptoms in the preceding week (no preinfarction angina group). Culprit plaque was classified as plaque rupture (PR) or intact fibrous cap (IFC), as previously described. Prati thrombus score was calculated, and the prevalence of calcification, neovascularization, and OCT-defined macrophage accumulation was assessed. Results Patients with preinfarction angina showed a significantly higher prevalence of IFC than PR, while those without preinfarction angina showed a significantly higher prevalence of PR than IFC (Figure). PR in patients with preinfarction angina were more frequently associated with macrophage accumulation, while those in patients without preinfarction angina were not (Figure). White thrombus tended to be more frequent in patients with preinfarction angina than in those without (85.7% vs. 63.6%, p=0.097), and Prati thrombus score tended to be lower [22.0 (15.8–30.3) vs. 38.5 (12.8–67.5), p=0.145]. Calcifications were significantly less frequent in patients with preinfarction angina than in those without (22.0% vs. 40.4%, p=0.045), while neovascularization tended to be more frequent (58.0% vs. 42.3%, p=0.113). Conclusions Patients with preinfarction angina have a distinct culprit plaque phenotype, frequently characterized by IFC and a relatively lower thrombotic burden, probably reflecting a prevalence of reparative mechanisms and spontaneous thrombolytic activity in these patients.