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

Background and aims: Transvenous lead extraction (TLE) has become a pivotal part of a comprehensive lead management strategy, dealing with a continuously increasing demand. Nonetheless, literature about the long-term impact of TLE on survivals still lacking. Given these knowledge gaps, the aim of our study was to analyse very long-term mortality in patients undergoing TLE in public health perspective. Methods: This prospective, single-centre, observational study enrolled consecutive patients with cardiac implantable electronic device (CIED) who underwent TLE, from January 2005 to January 2021. The main goal was to establish the independent predictors of very long-term mortality after TLE. We also aimed at assessing procedural and hospitalization related costs. Results: We enrolled 435 patients (mean age 70 ± 12 years, with mean lead dwelling time 6.8 ± 16.7 years), with prevalent infective indication to TLE (92%). Initial success of TLE was achieved in 98% of population. After a median follow-up of 4.5 years (range 1 month- 15.5 years),150 of the 435enrolled patients (34%) died. At multivariate analysis, death was predicted by: age (≥ 77 years, OR: 2.55, CI: 1.8-3.6, pConclusions: Our study identified three predictors of long-term mortality in a high-risk cohort of patients with a cardiac device infection, undergoing successful TLE. The future development of a mortality risk score before might impact on public health strategy.

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

Background A sizeable number of patients with a diagnosis of non-ST segment elevation acute coronary syndrome show non-obstructive coronary artery disease. In this study we assessed whether differences in vascular and cardiac autonomic function exist between non-ST segment elevation acute coronary syndrome patients with obstructive or non-obstructive coronary artery disease. Methods and results Systemic endothelium-dependent and independent vascular dilator function (assessed by flow-mediated dilation and nitrate-mediated dilation of the brachial artery, respectively) and cardiac autonomic function (assessed by time-domain and frequency-domain heart rate variability parameters) were assessed on admission in 120 patients with a diagnosis of non-ST segment elevation acute coronary syndrome. Patients were divided into two groups according to coronary angiography findings: (a) 59 (49.2%) with obstructive coronary artery disease (≥50% stenosis in any epicardial arteries); (b) 61 (50.8%) with non-obstructive coronary artery disease. No significant differences between the two groups were found in both flow-mediated dilation (5.03 ± 2.6 vs. 5.40 ± 2.5%, respectively; P = 0.37) and nitrate-mediated dilatation (6.79 ± 2.8 vs. 7.30 ± 3.4%, respectively; P = 0.37). No significant differences were also observed between the two groups both in time-domain and frequency-domain heart rate variability variables, although the triangular index tended to be lower in obstructive coronary artery disease patients (30.2 ± 9.5 vs. 33.9 ± 11.6, respectively; P = 0.058). Neither vascular nor heart rate variability variables predicted the recurrence of angina, requiring emergency room admission or re-hospitalisation, during 11.3 months of follow-up. Conclusions Among patients admitted with a diagnosis of non-ST segment elevation acute coronary syndrome we found no significant differences in systemic vascular dilator function and cardiac autonomic function between those with obstructive coronary artery disease and those with non-obstructive coronary artery disease.

Aims Transvenous lead extraction (TLE) has become a pivotal part of a comprehensive lead management strategy, dealing with a continuously increasing demand. Nonetheless, literature about long-term outcomes and the impact of a new device implantation on survival is still lacking. Given these knowledge gaps, the aim of our study was to analyse reimplantation and both early and long-term mortality in patients undergoing TLE, even in a public health perspective, specifically clarifying concerns about reimplantation. Methods This prospective, single-centre, observational, real-world registry consecutively enrolled patients (pts) with cardiac implantable electronic device who underwent TLE at our Hospital, from January 2005 to September 2020. The primary endpoint was to analyse major adverse cardiovascular events (MACEs) in both re-implanted (R Group) and non reimplanted (NR Group); secondary end-point was long-term (after discharge) mortality of the whole cohort, in order to investigate long-term mortality predictors. Results We enrolled high-risk cohort of 451 pts (mean population age 70 ± 12, with lead dwelling time 81.7 ± 201.2 months) at baseline findings: 92% of pts had an evidence of device infection, a generally impaired heart function with mean left ventricular ejection fraction (LVEF) 44 ± 13% and high rates of comorbidities (15% of pts with hypertension+ diabetes mellitus + renal failure). Three-hundred thirteen (72%) pts were reimplanted, using endocardiac leads in 86% and epicardial leads in 14%. Total MACEs rate was higher in R Group versus NR Group (64% versus 28%, P ≤ 0.001, CI 95%, respectively). In particular, rehospitalizations occurred more frequently in reimplanted population (R group 43% versus NR group 13%, P = 0.001, CI 95%). Long-term mortality rate was 34% (150 pts) at a mean follow up of 5.2 years. The leading contributor to long-term mortality was represented by multiple non-communicable chronic diseases (62%), being sepsis responsible for only 4% of long-term mortality, with a clear evidence of reduced infective burden after TLE and complete antibiotic therapy. At multivariate analysis, we found three independent predictors of long-term mortality: advanced age (> 77 years, OR 1.04, CI 1.02–1.06, P < 0.001), renal failure (eGFR Conclusions In patients undergoing TLE for infective indications, our study identified the reimplantation group as high risk group for adverse events before discharge. On the other hand, advanced age, renal failure and systolic dysfunction, as independent predictors of long-term mortality, could be evaluated as a predictive score to assess the mortality risk before the procedure of TLE.

Aims In ST-elevation myocardial infarction (STEMI), subtle tissutal changes in remote myocardium predict long-term left ventricular (LV) remodelling and prognosis, independently of infarct size and microvascular obstruction. Whether there is a subclinical dysfunction of remote myocardium, detectable by longitudinal strain (LS) at echocardiography, and whether it varies in different locations of STEMI and with adenosine (ADO) challenge, is still unknown. Methods and results Fifty-three patients (age 65 ± 12.5 years, 44 male, 20 anterior and 33 non-anterior, P = 0.01) underwent rest/stress echocardiography at 7 ± 2 days after successfully treated STEMI, and at 6-months follow-up. Global LS (GLS), ischaemic and remote LS (iLS and rLS) were analysed in anterior and non-anterior STEMI. Both at rest and at follow-up, GLS was stratified by ejection fraction (EF) into three groups: EF Conclusions In the subacute phase, anterior STEMI shows the worst impairment of LS in both ischaemic and remote regions. Strain reserve to ADO is absent in remote myocardium, as well as in ischaemic zone, regardless of MI location. Global, ischaemic and remote LS may improve at follow-up.

Aims Atrial and ventricular tachyarrhythmias are common among patients with adult congenital heart disease (ACHD) and can impair quality of life and prognosis. Catheter ablation is often the main treatment option in this population, despite anatomical hurdles. Substrate mapping findings have not been thoroughly investigated as predictors of arrhythmia recurrence success and cardiovascular clinical outcome after ablation. We sought to determine the prognostic value of myocardial scar and chamber enlargement detected at electroanatomical mapping in ACHD patients undergoing catheter ablation of tachyarrhythmias. Methods and results Consecutive ACHD patients undergoing catheter ablation of atrial and ventricular tachycardias using different electroanatomical mapping systems were retrospectively identified from a hospital-based database. Scar extent detected at the electroanatomical mapping, as well as the total mapped area, was calculated. Arrhythmia recurrence, hospitalization for cardiovascular (CV) reasons, and a combined endpoint (arrhythmia recurrence and/or CV hospitalization) were evaluated during the follow-up. The relationship between the aforementioned electroanatomical findings and the patients’ outcome was assessed. Twenty patients (12 male, 60%; mean age 40 ± 11 years) undergoing atrial (n = 14; 70%) or ventricular (n = 6; 30%) tachyarrhythmia were included. Acute procedural success (arrhythmia termination and/or no reinduction) was achieved in all the patients. At a mean follow-up of 171 ± 135 weeks, eight patients (40%) had arrhythmia recurrence (4/6 in the ventricular tachycardia group, 67%, 4/14 in the atrial tachycardia group, 28%). Patients with arrhythmia recurrence had a more extensive bipolar scar (P = 0.029) and a larger total mapped area (P = 0.03) than patients without recurrence, and so did the patients with the composite endpoint (P = 0.029 and P = 0.03, respectively). Patients with subsequent CV hospitalization had a larger total mapped area than patients without CV hospitalization (P = 0.017). The presence of a bipolar scar ≥22.95 cm2 predicted arrhythmia relapse (0.039) at the multivariate analysis. Conclusions Patients with ACHD show a high recurrence rate after catheter ablation, especially for ventricular tachycardias. A large bipolar scar at the electroanatomical mapping and total mapped area predict arrhythmia recurrence, likely due to the presence of more extensive reentry circuits. A large total mapped area, which may reflect a greater disease severity, predicts both arrhythmia recurrence and CV hospitalizations. Early referral of ACHD patients for catheter ablation may be a sound strategy in order to perform the procedure in the setting of less advanced heart disease.

Permanent pacemaker implantation (PPI) represents a frequent complication after transcatheter aortic valve implantation (TAVI) due to atrio-ventricular (AV) node injury. Predictors of early AV function recovery were investigated. We analyzed 50 consecutive patients (82 ± 6 years, 58% males, EuroSCORE: 7.8 ± 3.3%, STS mortality score: 5 ± 2.8%). Pacemaker interrogations within 4–6 weeks from PPI were performed to collect data on AV conduction. The most common indication of PPI was persistent third-degree (44%)/high-degree (20%) AV block/atrial fibrillation (AF) with slow ventricular conduction (16%) after TAVI. At follow-up, 13 patients (26%) recovered AV conduction (i.e., sinus rhythm with stable 1:1 AV conduction/AF with a mean ventricular response >50 bpm, associated with a long-term ventricular pacing percentage < 5%). At multivariate analysis, complete atrio-ventricular block independently predicted pacemaker dependency at follow-up (p = 0.019). Patients with persistent AV dysfunction showed a significant AV conduction time prolongation after TAVI (PR interval from 207 ± 50 to 230 ± 51, p = 0.02; QRS interval from 124 ± 23 to 147 ± 16, p < 0.01) compared to patients with recovery, in whom AV conduction parameters remained unchanged. Several patients receiving PPI after TAVI have recovery of AV conduction within a few weeks. Longer observation periods prior to PPI might be justified, and algorithms to minimize ventricular pacing should be utilized whenever possible.

Background and aims Diabetes mellitus (DM) is a risk factor for left ventricle (LV) diastolic dysfunction. Aim of this study was to investigate whether endothelial and/or autonomic dysfunction are associated with LV diastolic dysfunction in DM patients. Methods We studied 84 non-insulin-dependent type II DM (T2DM) patients with no heart disease by assessing: 1) LV diastolic function by echocardiography; 2) peripheral vasodilator function, by measuring flow-mediated dilation (FMD) and nitrate-mediate dilation (NMD); 3) heart rate variability (HRV) on 24-hour Holter electrocardiographic monitoring. Results Twenty-five patients (29.8%) had normal LV diastolic function, while 47 (55.9%) and 12 (14.3%) showed a mild and moderate/severe diastolic dysfunction, respectively. FMD in these 3 groups was 5.25±2.0, 4.95±1.6 and 4.43±1.8% (p=0.42), wherease NMD was 10.8±2.3, 8.98±3.0 and 8.82±3.2%, respectively (p=0.02). HRV variables did not differ among groups. However, the triangular index tended to be lower in patients with moderate/severe (p=0.09) and a significant correlation was found between the E/e' ratio and both the triangular index (r=-0.26; p=0.022) and LF amplitude (r=-0.29; p=0.011). Conclusions In T2DM patients an impairment of endothelium-independent, but not endothelium-dependent, dilatation seems associated with LV diastolic dysfunction. The possible role of cardiac autonomic dysfunction in diastolic dysfunction deserves investigation in larger populations of patients. This article is protected by copyright. All rights reserved.

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

Community-acquired pneumonia (CAP) is complicated by cardiovascular events as myocardial infarction and stroke but the underlying mechanism is still unclear. We hypothesized that endothelial dysfunction may be implicated and that endotoxemia may have a role.Fifty patients with CAP and 50 controls were enrolled. At admission and at discharge, flow-mediated dilation (FMD), serum levels of endotoxins and oxidative stress, as assessed by serum levels of nitrite/nitrate (NOx) and isoprostanes, were studied.At admission, a significant difference between patients with CAP and controls was observed for FMD (2.1±0.3 vs 4.0±0.3%, p0.001), serum endotoxins (157.8±7.6 vs 33.1±4.8pg/ml), serum isoprostanes (341±14 vs 286±10 pM, p=0.009) and NOx (24.3±1.1 vs 29.7±2.2μM). Simple linear correlation analysis showed that serum endotoxins significantly correlated with Pneumonia Severity Index score (Rs=0.386, p=0.006). Compared to baseline, at discharge CAP patients showed a significant increase of FMD and NOx (from 2.1±0.3 to 4.6±0.4%, p0.001 and from 24.3±1.1 to 31.1±1.5μM, p0.001, respectively) and a significant decrease of serum endotoxins and isoprostanes (from 157.8±7.6 to 55.5±2.3pg/ml, p0.001, and from 341±14 to 312±14 pM, p0.001, respectively). Conversely, no changes for FMD, NOx, serum endotoxins and isoprostanes were observed in controls between baseline and discharge. Changes of FMD significantly correlated with changes of serum endotoxins (Rs=-0.315; p=0.001).The study provides the first evidence that CAP is characterized by impaired FMD with a mechanism potentially involving endotoxin production and oxidative stress.

Background: Sex and gender-related factors have been under-investigated as relevant determinants of health outcomes across non-communicable chronic diseases. Poor medication adherence results in adverse clinical outcomes and sex differences have been reported among patients at high cardiovascular risk, such as diabetics. The effect of diabetes and gender-related factors on medication adherence among women and men at high risk for ischemic heart disease (IHD) has not yet been fully investigated. Aim: To explore the role of sex, gender-related factors, and diabetes in pre-admission medication adherence among patients hospitalized for IHD. Materials and Methods: Data were obtained from the Endocrine Vascular disease Approach (EVA) (ClinicalTrials.gov Identifier: NCT02737982), a prospective cohort of patients admitted for IHD. We selected patients with baseline information regarding the presence of diabetes, cardiovascular risk factors, and gender-related variables (i.e., gender identity, gender role, gender relations, institutionalized gender). Our primary outcome was the proportion of pre-admission medication adherence defined through a self-reported questionnaire. We performed a sex-stratified analysis of clinical and gender-related factors associated with pre-admission medication adherence. Results: Two-hundred eighty patients admitted for IHD (35% women, mean age 70), were included. Around one-fourth of the patients were low-adherent to therapy before hospitalization, regardless of sex. Low-adherent patients were more likely diabetic (40%) and employed (40%). Sex-stratified analysis showed that low-adherent men were more likely to be employed (58 vs. 33%) and not primary earners (73 vs. 54%), with more masculine traits of personality, as compared with medium-high adherent men. Interestingly, women reporting medication low-adherence were similar for clinical and gender-related factors to those with medium-high adherence, except for diabetes (42 vs. 20%, p = 0.004). In a multivariate adjusted model only employed status was associated with poor medication adherence (OR 0.55, 95%CI 0.31–0.97). However, in the sex-stratified analysis, diabetes was independently associated with medication adherence only in women (OR 0.36; 95%CI 0.13–0.96), whereas a higher masculine BSRI was the only factor associated with medication adherence in men (OR 0.59, 95%CI 0.35–0.99). Conclusion: Pre-admission medication adherence is common in patients hospitalized for IHD, regardless of sex. However, patient-related factors such as diabetes, employment, and personality traits are associated with adherence in a sex-specific manner.

Management of patients presenting to the Emergency Department with chest pain is continuously evolving. In the setting of acute coronary syndrome, the availability of high-sensitivity cardiac troponin assays (hs-cTn) has allowed for the development of algorithms aimed at rapidly assessing the risk of an ongoing myocardial infarction. However, concerns were raised about the massive application of such a simplified approach to heterogeneous real-world populations. As a result, there is a potential risk of underdiagnosis in several clusters of patients, including women, for whom a lower threshold for hs-cTn was suggested to be more appropriate. Implementation in clinical practice of sex-tailored cut-off values for hs-cTn represents a hot topic due to the need to reduce inequality and improve diagnostic performance in females. The aim of this review is to summarize current evidence on sex-specific cut-off values of hs-cTn and their application and usefulness in clinical practice. We also offer an extensive overview of thresholds reported in literature and of the mechanisms underlying such differences among sexes, suggesting possible explanations about debated issues.

Platelet activation seems to be implicated in the cardiovascular events occurring in patients with community-acquired pneumonia (CAP) but the underlying mechanism is still unclear. Aim of the study was to assess the mechanism involved in platelet activation in CAP patients.Two-hundred-seventy-eight consecutive patients hospitalized for CAP were recruited and followed-up until discharge. Hospitalized patients matched for sex, age and comorbidities but without acute infectious diseases were used as controls.At hospital admission patients disclosed enhanced plasma levels of sP-selectin, a maker of in-vivo platelet activation, serum sNOX2-dp, a marker of NADPH-oxidase activation, serum Lipopolysaccharide (LPS) and serum zonulin, a marker of gut permeability, compared to controls (p 0.001). Baseline sP-selectin was independently associated to serum LPS, sNOX2-sp and Pneumonia Severity Index score (p 0.001). Plasma sP-selectin, serum sNOX2-dp, LPS and zonulin coincidentally decreased at hospital discharge (p 0.001). An in vitro study showed that LPS, at concentration similar to that found in CAP patients, induced sP-selectin release by agonist-activated platelets, a phenomenon that was counteract by treating cells with gp91ds-tat, a specific inhibitor of NOX2.CAP patients display enhanced platelet activation, which is related to LPS-mediated NOX2 activation. Enhanced gut permeability seems be implicated in enhancing circulating levels of LPS.

Community-acquired pneumonia (CAP) is complicated by cardiac events in the early phase of the disease. Aim of this study was to assess if these intrahospital cardiac complications may account for overall mortality and cardiovascular events occurring during a long-term follow-up. Three hundred one consecutive patients admitted to the University-Hospital, Policlinico Umberto I, with community-acquired pneumonia were prospectively recruited and followed up for a median of 17.4 months. Primary end point was the occurrence of death for any cause, and secondary end point was the occurrence of cardiovascular events (cardiovascular death, nonfatal myocardial infarction [MI], and stroke). During the intrahospital stay, 55 patients (18%) experienced a cardiac complication. Of these, 32 had an MI (29 non-ST-elevation MI and 3 ST-elevation MI) and 30 had a new episode of atrial fibrillation (7 nonmutually exclusive events). During the follow-up, 89 patients died (51% of patients with an intrahospital cardiac complication and 26% of patients without, p0.001) and 73 experienced a cardiovascular event (47% of patients with and 19% of patients without an intrahospital cardiac complication, p0.001). A Cox regression analysis showed that intrahospital cardiac complications, age, and Pneumonia Severity Index were significantly associated with overall mortality, whereas intrahospital cardiac complications, age, hypertension, and diabetes were significantly associated with cardiovascular events during the follow-up. In conclusion, this prospective study shows that intrahospital cardiac complications in the early phase of pneumonia are associated with an enhanced risk of death and cardiovascular events during long-term follow-up.