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Introduction Left atrial appendage (LAA) is a finger-like muscular extension of the left atrium (LA). It acts as blood reservoir, modulates LA pressure and elicits adaptive responses to stress. Several LAA shapes and variants have been described. We report a case of congenital absence of LAA diagnosed by transesophageal echocardiography (TEE) and confirmed by computed tomography (CT). Case report A 55-year-old male patient with history of hypertension was admitted to our hospital for an episode of atrial fibrillation (AF). TEE was performed and showed normal LA volume, absence of thrombi and spontaneous echo contrast in the LA, but, despite acquiring three-dimensional (3D) en-face views, we were unable to identify LAA. Congenital absence of LAA was suspected and multidetector cardiac CT confirmed the abnormality. Discussion Congenital absence of LAA is an extremely rare condition: only eighteen cases were described on a review of the literature published in 2020. Associations with other congenital abnormalities or with atrial fibrillation have been reported, but a causal relationship cannot be established. Multiple imaging modalities can be used to define the anatomy and function of LAA, to detect or rule out in situ thrombosis and to guide catheter-based therapies, but the most widely used technique is TEE. Among intracardiac thrombi in patients with non-valvular atrial fibrillation, more than 90% are identified in the LAA, meaning that the remaining 10% may develop in other sites of the LA. The congenital absence of LAA could be considered similar to LAA percutaneous occlusion or surgical exclusion; because of the few published randomized controlled trials, the current ESC guidelines on atrial fibrillation are unclear about the true thrombotic risk in these cases. Since LAA percutaneous occlusion is actually indicated only in cases of contraindications for long-term anticoagulant treatment, in our opinion in patients with non-valvular AF, LAA congenital absence, high stroke risk and low bleeding risk, anticoagulant therapy should be considered. Conclusion Congenital absence of LAA is an extremely rare condition and its pathophysiological role, especially with regard to antithrombotic therapy in patients with AF, is still not well defined.

Ejection fraction (EF) is still widely used to categorize heart failure (HF) patients but has limitations. Global longitudinal strain (GLS) has emerged as a new prognosticator in HF, independent of EF.We investigated the incremental predictive benefit of GLS over different risk profiles as identified by automated cluster analysis of simple echocardiographic parameters.In 797 HFrEF patients (age 66 ± 12y; mean EF 30 ± 7%), unsupervised cluster analysis of 10 routine echocardiographic variables (without GLS) was performed. Median follow-up was 37 months. End-point was all-cause mortality. Association between risk profiles, GLS, and mortality was assessed by Cox proportional-hazard modeling with interaction term. Cluster analysis allocated patients to 3 different risk phenogroups (PG): PG-1 (mild diastolic dysfunction [DD], moderate systolic dysfunction, no pulmonary hypertension, normal right ventricular [RV] function); PG-2 (moderate DD, mild pulmonary hypertension, normal RV function); PG-3 (severe DD, advanced systolic dysfunction, pulmonary hypertension, RV dysfunction). Compared to PG-1, PG-2 and PG-3 showed increased adjusted-hazard ratio (1.71; 95% CI:1.05-2.77, P = 0.30; and 2.58; 95% CI:1.50-4.44, P 0.001, respectively). GLS was independently associated with outcome in the whole population (adjusted-HR: 1.11; 95% CI: 1.05-1.17, P = 0.001); however, profile membership modified the relationship between GLS and outcome which was no longer significant in PG-3 (P for interaction = 0.003).Within HFrEF populations, clustering of routine echocardiography parameters can automatically identify patients with different risk profiles; further assessment by GLS may be useful for patients with not advanced disease.

Coronary artery disease is a major underlying etiology for heart failure. The role of coronary microvascular disease, and endothelial dysfunction, in the pathophysiology of heart failure is poorly appreciated. Endothelial dysfunction, induced by oxidative stress, contributes to the development of heart failure. Alterations of endothelial function and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway are involved in the pathophysiology of heart failure with both reduced and preserved ejection fraction. Indeed, an altered endothelium dependent vasodilatation, causing repeated episodes of ischemia/reperfusion, can induce a chronic stunned myocardium with systolic dysfunction and an increased diastolic stiffness with diastolic dysfunction. Moreover, the altered NO-cGMP pathway directly affects myocardial homeostasis. Endothelial dysfunction is associated with worse prognosis and higher rate of cardiovascular events. Potential therapeutic strategies targeting the NO-cGMP pathway in patients with HF will be discussed in this review article. Although clinical data are still inconclusive, the NO-cGMP pathway represents a promising target for therapy.

Background Patients with heart failure undergoing cardiac resynchronization therapy with or without defibrillator function may exhibit recovery of left ventricular ejection fraction (LVEF) during follow-up. Mechanical dispersion (MD; the SD of time to peak longitudinal strain by two-dimensional speckle-tracking echocardiography) is a known predictor of life-threatening ventricular arrhythmias (VAs). Relationships among LVEF recovery, changes in MD, and incidence of VA are still not extensively investigated. Methods In this retrospective study, recipients of cardiac resynchronization therapy defibrillation (n = 183) or implantable cardioverter-defibrillators only (n = 87) underwent conventional and speckle-tracking echocardiography, both at baseline and after 10 to 12 months, and were followed clinically. Both a ≥10% increase in LVEF and a final LVEF > 35% defined echocardiographic response (EchoResp). Reduction in MD ≥10 msec defined MD response (MDResp). Risk for appropriate implantable cardioverter-defibrillator therapy for VAs was assessed using a multivariable Cox hazard model. Results The prevalence of EchoResp+ and MDResp+ was 39% and 46%, respectively. During follow-up (49.8 ± 33.5 months), 74 VA events occurred. The incidence rate (per 100 patient-years) of VAs was lowest in the EchoResp+/MDResp+ group (1.66%; 95% CI, 0.69%-3.99%), highest in the EchoResp−/MDResp− group (12.8%; 95% CI, 9.53%-17.2%; P 71.4 msec) was associated with VAs independent of whether final LVEF was below or above the guideline-reported cutoff of 35% (P Conclusions Among ICD recipients, improvements in both left ventricular function and MD are associated with reduced risk for VAs. In patients whose follow-up LVEFs improved to >35%, risk for VAs, although substantially decreased, remained elevated in the presence of still elevated MD.

BACKGROUND: In a prior trial of late sodium channel inhibition (ranolazine) among symptomatic subjects without obstructive coronary artery disease (CAD) and limited myocardial perfusion reserve index (MPRI), we observed no improvement in angina or MPRI, overall. Here we describe the clinical characteristics and myocardial perfusion responses of a pre-defined subgroup who had coronary flow reserve (CFR) assessed invasively. METHODS: Symptomatic patients without obstructive CAD and limited MPRI in a randomized, double-blind, crossover trial of ranolazine vs. placebo were subjects of this prespecified substudy. Because we had previously observed that adverse outcomes and beneficial treatment responses occurred in those with lower CFR, patients were subgrouped by CFR

Objectives The aim of this study was to assess the relationship between gait speed and the risk for death and/or hospital admission in older patients with heart failure (HF). Background Gait speed is a reliable single marker of frailty in older people and can predict falls, disability, hospital admissions, and mortality. Methods In total, 331 community-living patients ≥70 years of age (mean age 78 ± 6 years, 43% women, mean ejection fraction 35 ± 11%, mean New York Heart Association functional class 2.7 ± 0.6) in stable condition and receiving optimized therapy for chronic HF were prospectively enrolled and followed for 1 year. Gait speed was measured at the usual pace over 4 m, and cutoffs were defined by tertiles: ≤0.65, 0.66 to 0.99, and ≥1.0 m/s. Results There was a significant association between gait speed tertiles and 1-year mortality: 38.3%, 21.9%, and 9.1% (p Conclusions Gait speed is independently associated with death, hospitalization for HF, and all-cause hospitalization and improves risk stratification in older patients with HF evaluated using the Cardiac and Comorbid Conditions Heart Failure score. Assessment of frailty using gait speed is simple and should be part of the clinical evaluation process.

Background Left atrial (LA) volume is a marker of cardiac remodeling and prognosis in heart failure (HF) with reduced ejection fraction (EF), but LA function is rarely measured or characterized. We investigated determinants and prognostic impact of LA reservoir function in patients with HF with reduced EF. Methods and Results In 405 patients with stable HF with reduced EF (EF, ≤40%) in sinus rhythm, we assessed LA reservoir function by both LA total EF (by phasic volume changes) and peak atrial longitudinal strain (PALS; by speckle tracking echocardiography); LA functional index was also calculated. During follow-up (median, 30 months; Q1-Q3, 13-52), 139 patients (34%) reached the composite end point (all-cause death/HF hospitalization). Median PALS was 15.5% (interquartile range, 11.2-20.6). By univariable analysis, all LA function parameters significantly predicted outcome ( P0.01 for all), with PALS showing the highest predictive accuracy (area under the curve, 0.75; sensitivity, 73%; specificity, 70%). Impaired PALS was associated with greater left ventricular and LA volumes, worse left ventricular EF, left ventricular global longitudinal strain, right ventricular systolic function, and more severe diastolic dysfunction. After multivariable adjustment (including LA volume and left ventricular global longitudinal strain), PALS, but not LA total EF or LA functional index, remained significantly associated with outcome (hazard ratio per 1-SD decrease, 1.38; 95% CI, 1.05-1.84; P=0.030). Adding PALS to a base model, including age, sex, LA volume, EF, E/E' ratio, and global longitudinal strain, provided incremental predictive value (continuous net reclassification improvement, 0.449; P=0.0009). Conclusions In HF with reduced EF, assessment of LA reservoir function by PALS allows powerful prognostication, independently of LA volume and left ventricular longitudinal contraction.

Background Left atrial (LA) volume is a marker of cardiac remodeling and prognosis in heart failure (HF) with reduced ejection fraction (EF), but LA function is rarely measured or characterized. We investigated determinants and prognostic impact of LA reservoir function in patients with HF with reduced EF. Methods and Results In 405 patients with stable HF with reduced EF (EF, ≤40%) in sinus rhythm, we assessed LA reservoir function by both LA total EF (by phasic volume changes) and peak atrial longitudinal strain (PALS; by speckle tracking echocardiography); LA functional index was also calculated. During follow-up (median, 30 months; Q1–Q3, 13–52), 139 patients (34%) reached the composite end point (all-cause death/HF hospitalization). Median PALS was 15.5% (interquartile range, 11.2–20.6). By univariable analysis, all LA function parameters significantly predicted outcome ( P P =0.030). Adding PALS to a base model, including age, sex, LA volume, EF, E/E′ ratio, and global longitudinal strain, provided incremental predictive value (continuous net reclassification improvement, 0.449; P =0.0009). Conclusions In HF with reduced EF, assessment of LA reservoir function by PALS allows powerful prognostication, independently of LA volume and left ventricular longitudinal contraction.

Global right ventricular (RV) longitudinal strain (RVGLS) and free wall RV longitudinal strain (RVFWS) have both been advocated as sensitive tools to evaluate RV function and predict prognosis in patients with heart failure and reduced ejection fraction (HFrEF). However, because the interventricular septum is an integral part of the left ventricle (LV) also, RVGLS might be influenced by LV dysfunction. Thus, we compared the prognostic performance of either RV strain parameter in HFrEF patients, also taking into account the degree of LV systolic dysfunction.In 288 prospectively enrolled outpatients with stable HFrEF, RVGLS and RVFWS were assessed by speckle-tracking and LV systolic function by global longitudinal strain and LV ejection fraction. Patients were followed up for 30.2 ± 23.0 months; the primary endpoint was all-cause death/heart failure-related hospitalization. Prognostic performance was assessed by C-statistic and net reclassification improvement.There were 95 events during follow-up. By univariable analysis, both RVGLS (hazard ratio × 1 SD, 1.60; 95% CI, 1.29-1.99; P .0001) and RVFWS (hazard ratio × 1 SD, 1.82; 95% CI, 1.45-2.29; P .0001) were associated with outcome, and both remained significant after correction for EMPHASIS risk score, New York Heart Association class, natriuretic peptides, and therapy. However, after further correction for LV systolic function parameters, only RVFWS remained significantly associated with outcome (P .01). A basic prediction model was improved by adding RVFWS (net reclassification improvement 0.390; P .05), but not RVGLS.Although both RVGLS and RVFWS have prognostic value, RVFWS better predicts outcome in HFrEF patients, mainly because it is less influenced by LV longitudinal dysfunction.

Background and aims Elevated serum uric acid (sUA) concentrations have been associated with worse prognosis in heart failure (HF) but little is known about elderly patients. We aimed to assess long-term additive prognostic value of sUA in elderly patients hospitalized for HF. Methods and results Clinical and echocardiographic characteristics of 310 consecutive elderly patients hospitalized for HF were collected. During index period, 206 had sUA concentrations available, which were obtained within 24 h prior to discharge; 10 patients were lost to follow-up, leaving 196 patients available. Patients had a median age of 77 (IQR 69–83) years, and were mostly male (64.5%). sUA ranges for tertiles I–III were: 1.5–6.1, 6.2–8.3, and 8.4–18.9 mg/dl, respectively. During a median follow-up of 27 months (IQR 10.5–39.5), 122 combined events occurred (87 deaths and 73 HF rehospitalizations). Four-year event-free survival for the combined endpoint was 46 ± 7% for tertile I, 34 ± 7% for tertile II, and 21 ± 5% for tertile III (P = 0.001). By multivariable Cox backward analysis, sUA was retained as a significant predictor. Compared with the lowest sUA tertile, tertile III showed a strong association with outcome, also after adjustment for other predictors (HR 1.84, 95% CI 1.16–2.93; P = 0.01). Importantly, addition of sUA to the other significant predictors of outcome resulted in improved risk classification (net reclassification improvement 0.19, P = 0.017). Conclusions High sUA at discharge is a strong predictor of adverse outcome in elderly hospitalized for HF, and it significantly improves risk classification. Measuring sUA can be a simple and useful tool to identify high-risk elderly hospitalized for HF.

Background— In heart failure (HF) with reduced ejection fraction, right ventricular (RV) impairment, as defined by reduced tricuspid annular plane systolic excursion, is a predictor of poor outcome. However, peak longitudinal strain of RV free wall (RVFWS) has been recently proposed as a more accurate and sensitive tool to evaluate RV function. Accordingly, we investigated whether RVFWS could help refine prognosis of patients with HF with reduced ejection fraction in whom tricuspid annular plane systolic excursion is still preserved. Methods and Results— A total of 200 patients with HF with reduced ejection fraction (age, 66±11 years; ejection fraction, 30±7%) with preserved tricuspid annular plane systolic excursion (>16 mm) underwent RV function assessment using speckle-tracking echocardiography to measure peak RVFWS. After a median follow-up period of 28 months, 62 (31%) patients reached the primary composite end point of all-cause death/HF rehospitalization. Median RVFWS was −19.3% (interquartile range, −23.3% to −15.0%). By lasso-penalized Cox-hazard model, RVFWS was an independent predictor of outcome, along with Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure-HF score, Echo-HF score, and severe mitral regurgitation. The best cutoff value of RVFWS for prediction of outcome was −15.3% (area under the curve, 0.68; P P P Conclusions— In patients with HF with reduced ejection fraction with preserved tricuspid annular plane systolic excursion, RV free-wall strain provides incremental prognostic information and improved risk stratification.

Myocardial reflectivity, as assessed by calibrated integrated backscatter (cIB) analysis, is a non-invasive surrogate for the amount of left ventricular (LV) fibrosis. The aim of this study was to assess the myocardial reflectivity pattern in patients with heart failure and preserved ejection fraction (HFpEF), and to evaluate its relationship with longitudinal systolic deformation of LV by 2D-speckle tracking echocardiography, and degree of diastolic dysfunction. Transthoracic echocardiography, myocardial Doppler-derived systolic (Sm) and early diastolic velocity (E'), global longitudinal strain (GLS), and tissue characterization by cIB, were obtained in 86 subjects, 46 with HFpEF, and 40 controls. GLS was significantly impaired in HFpEF patients (-15.4 ± 3.5 % vs -21.5 ± 2.9 % in controls; P

61 MicroRNA-216a: a cardiac-specific post-transcriptional regulator of capillary rarefaction associated with heart failure {#article-title-2} Background: While cardiomyocytes have been the main subject of extensive research in the past, the role of other cardiac cell types in the pathogenesis of heart failure received considerable less attention. Multiple other cell types, including fibroblasts, endothelial cells and vascular smooth muscle cells make up the heart and increasing evidence suggests that these cell types contribute to myocardial health and disease. Angiogenesis is an important adaptive mechanism of the myocardium to conditions of sustained increased demand. A select number of microRNAs were found to participate in post-myocardial angiogenesis but to date, it is unclear, however, if microRNAs regulate cardiac angiogenesis in the non-ischemic failing myocardium, which represents a clinically more relevant question. Purpose: Establish that non-coding RNAs are main orchestrators of vascular integrity and hemostasis in the heart and changes in expression of the non-coding RNA content in different cardiac cell types underlie defects in neovascularization and progression to heart failure. Results: To identify cardiac angiomiRs we recently completed a functional, genome-wide microRNA knockdown screen in cultured mouse cardiac microvascular endothelial cells. In this setup, we performed the scratch assay by fully automated scratch induction and image capturing and identified several candidate microRNAs. miR-216a, one of those candidates affecting endothelial cell migration, is consistently downregulated in a mouse model of cardiac pressure overload induced by transverse aortic constriction. We generated mice with a somatic gene deletion of miR-216a (miR-216-/-). Ablation of miR-216a induced dramatic effects on cardiac morphology and function. In addition to spontaneous development of pathological cardiac remodeling at baseline, miR-216-/- mice are also extremely sensitive to cardiac stress and die 1-2 weeks after pressure overload or develop severe cardiac phenotypes 3-4 weeks after myocardial infarction. Interestingly, the defects observed correlate with vascular defects including capillary rarefaction and reduced angiogen­­­­ic activity. By combining photoacoustics with high-frequency ultrasound we observed different levels of hypoxia throughout the cardiac tissue confirming lower oxygenation of the miR-216a-/- hearts. The observed effects of miR-216 modulation seem to be related to altered autophagic activity in cardiac endothelial cells. Conclusions: We identified a new angiogenesis-related gene regulatory network where miR-216a underlies the vascular changes associated with pathological cardiac remodeling and/or heart failure. # 62 Divergent effects of pre- and post-conditioning on microvascular function {#article-title-3} Background: A short period of ischemia/reperfusion (I/R) that occurs before a prolonged ischemia (preconditioning; preC) or at reflow (postconditioning; postC) reduces tissue necrosis through activation of regulatory kinases cascades, also reciprocally related, including the GPCR-PKG-PKC cascade and the RISK pathway. In this setting, an important role is played by nitric oxide (NO), which is also the main mediator of endothelium-dependent vasodilation. PreC may also protect microcirculation against I/R injury, while the impact of postC is less clear, and mechanism underlying these effects are not completely elucidated. Purpose: To study the influence of preC and postC on postichemic microcirculation, by specifically evaluating leukocyte recruitment and vasodilating reserve, and to correlate these effects with activation of regulatory kinases. Methods: In rats, cremaster muscle was prepared for in vivo videomicroscopy leaving vascular and neural connections intact. Animals were divided in 4 groups: 1- controls, in which muscle was subjected to 90 min of I and 90 min of R; 2- preC, in which preC was induced before I by 5 min of I and 10 min of R; 3- postC, in which postC was induced at R with 5 cycles of 10 seconds R and 5 seconds I; 4- sham, observed after surgery for an equivalent period of time. Leukocyte recruitment was monitored during I/R; at the end of R, vasodilating endothelium-dependent and -independent reserve was assessed by local superfusion with 10-4 µM acetylcholine and 10-5 µM sodium nitroprusside. Phosphorylation of ERK-1/2, Akt, eNOS, PKCe and GSK3β was measured by Western Blotting on muscle homogenates obtained at the end of experiment in a second set of experiments in which, to avoid possible confounding effects of acetylcholine and sodium nitroprusside on kinase activation, rats were divided in 4 groups as described above but vasodilating challenge was not performed. Results: I/R activated leukocyte recruitment (data not shown) and reduced vasodilating reserve, both endothelium-dependent and independent. Both preC and postC activated kinases and eNOS in a similar degree, and reduced leukocyte recruitment. However, only preC preserved vasodilating reserve (both endothelium-dependent and independent) (*=p