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Pulmonary vein isolation (PVI) with catheter ablation (CA) represents an effective therapy for atrial fibrillation (AF). Unfortunately, it is still not exempt from severe complications. The balance of risks and benefits should be assessed, and a patient-tailored approach is desirable. So far, several clinical and cardiac imaging parameters have been evaluated to investigate pre- and post-procedural features that could help clinicians in the selection of patients at high risk of a poor outcome after CA. This clinical and systematic review analyses the potential role of new LA parameters, such as LA reservoir strain, to predict AF recurrence after CA therapy. Notably, LA reservoir strain gains substantial clinical importance in patients with paroxysmal AF and when a low CHADS2-VASc score is retrieved. LA reservoir strain provides data concerning the risk of AF recurrence after PVI and, thus, in the management of long-term medical therapy in this patient's group.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome resulting from the interaction between cardiac diseases, comorbidities and ageing. HFpEF is characterised by the activation of neurohormonal axes, namely of the renin-angiotensin-aldosterone system and the sympathetic nervous system, although to a lesser extent compared with heart failure with reduced ejection fraction. This provides a rationale for neurohormonal modulation as a therapeutic approach for HFpEF. Nonetheless, randomised clinical trials have failed to demonstrate a prognostic benefit from neurohormonal modulation therapies in HFpEF, with the sole exception of patients with left ventricular ejection fraction in the lower range of normality, for whom the American guidelines suggest that such therapies may be considered. In this review, the pathophysiological rationale for neurohormonal modulation in HFpEF is summarised and the clinical evidence on pharmacological and nonpharmacological approaches backing current recommendations discussed., Competing Interests: Disclosure: The authors have no conflicts of interest to declare., (Copyright © 2023, Radcliffe Cardiology.)

Background : The gold-standard treatment for end-stage heart failure is heart transplantation, but the lack of organ donors remains an important limitation in this field. An accurate selection of marginal hearts is fundamental to increase organ availability. Purpose : In our study we analyzed if recipients receiving marginal donor (MD) hearts, selected by dipyridamole stress echocardiography according to the ADOHERS national protocol, had different outcomes compared to recipients with acceptable donor (AD) hearts. Methods : Data were collected and retrospectively analyzed from patients who received an orthotopic heart transplant at our institution between 2006 and 2014. Dipyridamole stress echo was performed on identified marginal donors and selected hearts were eventually transplanted. Clinical, laboratory and instrumental features of the recipients were evaluated and patients with homogenous baseline characteristics were selected. Results : Eleven recipients transplanted with a selected marginal heart and eleven recipients transplanted with an acceptable heart were included. Mean donor age was 41 ± 23. The median follow-up was 113 months (IQR 86-146 months). Age, cardiovascular risk and morpho-functional characteristics of the left ventricle were comparable between the two populations ( p > 0.05). Left atrial size was significantly higher in patients with marginal hearts (acceptable atrial volume: 23 ± 5 mL; marginal atrial volume: 38 ± 5 mL; p = 0.003). Acceptable donor recipients showed a higher impact of Cardiac Allograph Vasculopathy ( p = 0.019). No rejection differences were found between the two groups. Four patients deceased, three were standard donor recipients and one was from the marginal donor group. Conclusions : Our study shows how cardiac transplant (Htx) from selected marginal donor hearts through a non-invasive bedside technique can alleviate the shortage of organs without a difference in survival compared to acceptable donor hearts.

Background: Chronic total occlusion (CTO) revascularization is a major source of radiation for both patients and physicians. Therefore, efforts to minimize radiation during CTO percutaneous coronary intervention (PCI) are highly encouraged., Aims: To evaluate the impact of an Ultra Low fluoroscopic Dose Protocol (ULDP), based on 3.75 frames per second for the fluoroscopy and 7.5 frames per second for the cine acquisition, during CTO PCI., Methods: One hundred fifty consecutive patients who underwent CTO PCI were retrospectively enrolled. Eighty-five underwent standard dose protocol (SDP) and 65 ULDP. Radiation exposure and acute clinical outcomes were compared between groups. Results were stratified according to lesion complexity., Results: Patients undergoing ULDP, as compared to those undergoing SDP, showed a significant reduction of kerma area product, both for simple lesions (6861.0 vs. 13236.0 mGy × cm 2 ; p = 0.014) and complex lesions (CL) (8865.0 vs. 16618.0 mGy × cm 2 ; p < 0.001). Similarly, Air Kerma (AK) was lower when ULDP was used (1222.5 vs. 2015.0 cGy in SL, p = 0.134; 1499.0 vs. 2794.0 cGy in CL, p < 0.001). No significant differences were reported regarding procedural success and in-hospital major adverse cardiovascular events between groups. Notably, there was not any crossover from ULDO to SDP due to poor quality images. Interestingly, fluoroscopy time, procedural time and contrast volume was significantly lower in patients undergoing ULDP only for CLs., Conclusions: ULDP significantly reduces radiation exposure in the setting of high complexity procedures such as CTO PCI. This reduction seemed to be greater with increased procedural complexity and did not impact acute success or adverse clinical events., (© 2023 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Circulatory shock is a clinical condition characterized by hypotension and organ hypoperfusion, potentially fatal if the underlying cause is not promptly identified and corrected. Circulatory shock outcome is certainly conditioned from early diagnosis and early and adequate therapy. The aim of this review is to provide a tool for a rapid differential diagnosis among the various phenotypes of circulatory shock, based on the clinical, hemodynamic and biochemical profile. We also prompt to emphasize the role of multiparametric monitoring from the early phases of the management and the need to implement the time-dependent network to improve the outcome of these critical patients.

Background: The relief of congestion is crucial to improve heart failure (HF) patient's quality of life and prognosis. N-terminal-pro-brain natriuretic peptide (NT-proBNP) is a well-known marker of congestion, although with limited specificity. Peak atrial longitudinal strain (PALS) by speckle tracking echocardiography (STE) is an index of intracardiac pressure and HF prognosis. We aimed to determine the association between NT-proBNP and PALS and its prognostic implications in patients with HF., Methods: Patients hospitalized for de-novo or recurrent HF and outpatients with chronic HF were included in this retrospective study. Patients with missing data, previous cardiac surgery, non-feasible STE were excluded. Clinical, laboratory and echocardiographic data were collected. STE was performed on echocardiographic records. Primary endpoint was a combination of all-cause death and HF hospitalization., Results: Overall, 388 patients were included (172 acute HF, 216 chronic HF, mean age = 65 ± 12 years, 37% female). Mean LV ejection fraction = 31 ± 9%. Global PALS showed a significant inverse correlation with NT-proBNP in acute and chronic HF (all p < 0.001). During a median follow-up of 4 years, 180 patients reached the combined endpoint. NT-proBNP (AUC = 0.87) and global PALS (AUC = 0.82) were good predictors of the combined endpoint. Global PALS was the only independent predictor of the combined endpoint. Optimal risk stratification for the composite endpoint was provided combining PALS ≤15% and NTproBNP ≥874.5 ng/l., Conclusions: Global PALS is associated with NT-proBNP in acute and chronic HF and may be used as additional index of congestion to optimize therapeutic management. The combination of global PALS and NT-proBNP could enhance the prognostic stratification of HF., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background : Cardiac Magnetic Resonance (CMR) has a key role in subjects presenting with acute myocarditis, independent from left ventricular ejection fraction; it is widely used as a non-invasive imaging test for both diagnostic and prognostic purposes. However, poor data is available about the CMR-derived prognostic parameters of acute myocarditis with preserved ejection fraction (AMpEF). The aim of this study was to investigate the role of CMR in predicting outcomes in patients followed up for AMpEF, using a composite endpoint of all-cause mortality and hospitalization for heart failure (HF). Methods : We retrospectively enrolled 61 patients with diagnosed AMpEF. All patients underwent biohumoral, echocardiographic and CMR evaluation in the acute phase. Myocarditis was confirmed by Lake-Louis criteria assessed on CMR images. Mean follow-up was 4.8 ± 0.6 years during which a composite endpoint of all-cause mortality and hospitalization for HF was investigated. Results : The population was fairly homogeneous regarding baseline clinical features. In particular, no significant differences in age and main cardiovascular risk factors were found between patients with and without events at follow-up. Seven patients met the endpoint. They had significantly higher levels of circulating neutrophils in the acute phase (76 ± 7% vs. 61 ± 11%, p = 0.014) and a higher amount of left ventricular mass with delayed enhancement (DE-LVM, 18 (14-29.5) vs. 12 (8-16) g, p = 0.028). At Cox univariate analysis, DE-LVM was the only significant predictor of endpoint, regardless of the site of inflammation. Conclusions : DE-LVM can predict the composite endpoint of all-cause mortality and hospitalization for HF in a population of patients with AMpEF, representing a new added tool for prognostic stratification., Competing Interests: The authors declare no conflict of interest.

After initial strategies targeting inotropism and congestion, the neurohormonal interpretative model of heart failure (HF) pathophysiology has set the basis for current pharmacological management of HF, as most of guideline recommended drug classes, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, blunt the activation of detrimental neurohormonal axes, namely sympathetic and renin-angiotensin-aldosterone (RAAS) systems. More recently, sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, combining inhibition of RAAS and potentiation of the counter-regulatory natriuretic peptide system, has been consistently demonstrated to reduce mortality and HF-related hospitalization. A number of novel pharmacological approaches have been tested during the latest years, leading to mixed results. Among them, drugs acting directly at a second messenger level, such as the soluble guanylate cyclase stimulator vericiguat, or other addressing myocardial energetics and mitochondrial function, such as elamipretide or omecamtiv-mecarbil, will likely change the therapeutic management of patients with HF. Sodium glucose cotransporter 2 inhibitors, initially designed for the management of type 2 diabetes mellitus, have been recently demonstrated to improve outcome in HF, although mechanisms of their action on cardiovascular system are yet to be elucidated. Most of these emerging approaches have shifted the therapeutic target from neurohormonal systems to the heart, by improving cardiac contractility, metabolism, fibrosis, inflammation, and remodeling. In the present paper, we review from a pathophysiological perspective current and novel therapeutic strategies in chronic HF., (© 2021. The Author(s).)

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is associated with relevant morbidity and mortality. However, an evidence-based treatment is still absent. The heterogeneous definitions, differences in aetiology/pathophysiology, and diagnostic challenges of HFpEF made it difficult to define its epidemiological landmarks so far. Several large registries and observational studies have recently disclosed an increasing incidence/prevalence, as well as its prognostic significance. An accurate definition of HFpEF epidemiological boundaries and phenotypes is mandatory to develop novel effective and rational therapeutic approaches., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: The role of worsening renal function during acute heart failure (AHF) hospitalization is still debated. Very few studies have extensively evaluated the renal function (RF) trend during hospitalization by repetitive measurements., Objectives: To investigate the prognostic relevance of different RF trajectories together with the congestion status in hospitalized patients., Methods: This is a post hoc analysis of a multi-center study including 467 patients admitted with AHF who were screened for the Diur-AHF Trial. We recognized five main RF trajectories based on serum creatinine and estimated glomerular filtration rate (eGFR) behavior. According to the RF trajectories our sample was divided into 1-stable (S), 2-transient improvement (TI), 3-permanent improvement (PI), 4-transient worsening (TW), and 5-persistent worsening (PW). The primary outcome was the combined endpoint of 180 days including all causes of mortality and re-hospitalization., Results: We recruited 467 subjects with a mean congestion score of 3.5±1.08 and a median creatinine value of 1.28 (1.00-1.70) mg/dl, eGFR 50 (37-65) ml/min/m 2 and NTpro B-type natriuretic peptide (BNP) 7,000 (4,200-11,700) pg/ml. A univariate analysis of the RF pattern demonstrated that TI and PW patterns were significantly related to poor prognosis [HR: 2.71 (1.81-4.05); p < 0.001; HR: 1.68 (1.15-2.45); p = 0.007, respectively]. Conversely, the TW pattern showed a significantly protective effect on outcome [HR:0.34 (0.19-0.60); p < 0.001]. Persistence of congestion and BNP reduction ≥ 30% were significantly related to clinical outcome at univariate analysis [HR: 2.41 (1.81-3.21); p < 0.001 and HR:0.47 (0.35-0.67); p < 0.001]. A multivariable analysis confirmed the independently prognostic role of TI, PW patterns, persistence of congestion, and reduced BNP decrease at discharge., Conclusions: Various RF patterns during AHF hospitalization are associated with different risk(s). PW and TI appear to be the two trajectories related to worse outcome. Current findings confirm the importance of RF evaluation during and after hospitalization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Palazzuoli, Crescenzi, Luschi, Brazzi, Feola, Rossi, Pagliaro, Ghionzoli and Ruocco.)

Left ventricular assist devices (LVADs) have been representing a cornerstone therapy for patients with end-stage heart failure during the last decades. However, their use induces several pathophysiological modifications which are partially responsible for the complications that typically characterize these patients, such as right ventricular failure, thromboembolic events, as well as bleedings. During the last years, biomarkers involved in the pathways of neurohormonal activation, myocardial injury, adverse remodeling, oxidative stress and systemic inflammation have raised attention. The search and analysis of potential biomarkers in LVAD patients could lead to the identification of a subset of patients with an increased risk of developing these adverse events. This could then promote a closer follow-up as well as therapeutic modifications. Furthermore, it might highlight some new therapeutic pharmacological targets that could lead to improved long-term survival. The aim of this review is to provide current evidence on the role of different biomarkers in patients with LVAD, in particular highlighting their possible implications in clinical practice.

Background: The COVID-19 pandemic carries a high burden of morbidity and mortality worldwide. We aimed to identify possible predictors of in-hospital major cardiovascular (CV) events in COVID-19., Methods: We retrospectively included patients hospitalized for COVID-19 from 10 centers. Clinical, biochemical, electrocardiographic, and imaging data at admission and medications were collected. Primary endpoint was a composite of in-hospital CV death, acute heart failure (AHF), acute myocarditis, arrhythmias, acute coronary syndromes (ACS), cardiocirculatory arrest, and pulmonary embolism (PE)., Results: Of the 748 patients included, 141(19%) reached the set endpoint: 49 (7%) CV death, 15 (2%) acute myocarditis, 32 (4%) sustained-supraventricular or ventricular arrhythmias, 14 (2%) cardiocirculatory arrest, 8 (1%) ACS, 41 (5%) AHF, and 39 (5%) PE. Patients with CV events had higher age, body temperature, creatinine, high-sensitivity troponin, white blood cells, and platelet counts at admission and were more likely to have systemic hypertension, renal failure (creatinine ≥ 1.25 mg/dL), chronic obstructive pulmonary disease, atrial fibrillation, and cardiomyopathy. On univariate and multivariate analysis, troponin and renal failure were associated with the composite endpoint. Kaplan-Meier analysis showed a clear divergence of in-hospital composite event-free survival stratified according to median troponin value and the presence of renal failure (Log rank p < 0.001)., Conclusions: Our findings, derived from a multicenter data collection study, suggest the routine use of biomarkers, such as cardiac troponin and serum creatinine, for in-hospital prediction of CV events in patients with COVID-19.

Sarcoidosis is a systemic chronic granulomatous disease with significant morbidity and mortality. Although basic transthoracic echocardiography (TTE) is not recommended for the assessment of sarcoidosis, speckle tracking echocardiography (STE) has emerged as more sensitive for the early detection of cardiac sarcoidosis and its outcome. The aim of the study was to assess the utility of left atrial and left ventricular longitudinal STE for the prediction of major adverse cardiac events (MACE) and sarcoidosis relapses. We enrolled 172 consecutive patients with sarcoidosis who underwent TTE and pulmonary function tests (PFTs). All patients were followed for a sarcoidosis relapse and MACE. During a median follow-up of 2217 days, 8 deaths, 23 MACE and 36 sarcoidosis relapses were observed. LV global longitudinal strain (GLS) was significantly lower in patients with MACE ( p = 0.025). LV-GLS < 17.13% (absolute value) was identified as a fair predictor of MACE. Concerning the sarcoidosis control, TTE revealed a reduction of the LV ejection fraction ( p = 0.0432), tricuspid annular plane systolic excursion ( p = 0.0272) and global peak atrial longitudinal strain (PALS, p = 0.0012) in patients with relapses. PALS < 28.5% was the best predictor of a sarcoidosis relapse. Our results highlight a potential role of LV-GLS and PALS as prognostic markers in sarcoidosis, supporting the use of STE in the clinical management of these patients.

Primary mitral regurgitation (MR) is the second most common valvular disease, characterized by a high burden in terms of quality of life, morbidity, and mortality. Surgical treatment is considered the best therapeutic strategy for patients with severe MR, especially if they are symptomatic. However, pre-operative echocardiographic evaluation is an essential step not only for surgical candidate selection but also to avoid post-operative complications. Therefore, a strong collaboration between cardiologists and cardiac surgeons is fundamental in this setting. A meticulous pre-operative echocardiographic exam, both with transthoracic or transesophageal echocardiography, followed by a precise report containing anatomical information and parameters should always be performed to optimize surgical planning. Moreover, intraoperative transesophageal evaluation is often required by cardiac surgeons as it may offer additive important information with different hemodynamic conditions. Three-dimensional echocardiography has recently gained higher consideration and availability for the evaluation of MR, providing more insights into mitral valve geometry and MR mechanism. This review paper aims to realize a practical overview on the main use of basic and advanced echocardiography in MR surgical planning and to provide a precise checklist with reference parameters to follow when performing pre-operative echocardiographic exam, in order to aid cardiologists to provide a complete echocardiographic evaluation for MR operation planning from clinical and surgical point-of-view., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pastore, Mandoli, Sannino, Dokollari, Bisleri, D'Ascenzi, Cavigli, Pasquini, Lisi, Ghionzoli, Santoro, Miglioranza, Focardi, Patti, Valente, Mondillo and Cameli.)

Aims: The recent coronavirus disease 19 (COVID-19) pandemic outbreak forced the adoption of restraint measures, which modified the hospital admission patterns for several diseases. The aim of the study is to investigate the rate of hospital admissions for heart failure (HF) during the early days of the COVID-19 outbreak in Italy, compared with a corresponding period during the previous year and an earlier period during the same year., Methods and Results: We performed a retrospective analysis on HF admissions number at eight hospitals in Italy throughout the study period (21 February to 31 March 2020), compared with an inter-year period (21 February to 31 March 2019) and an intra-year period (1 January to 20 February 2020). The primary outcome was the overall rate of hospital admissions for HF. A total of 505 HF patients were included in this survey: 112 during the case period, 201 during intra-year period, and 192 during inter-year period. The mean admission rate during the case period was 2.80 admissions per day, significantly lower compared with intra-year period (3.94 admissions per day; incidence rate ratio, 0.71; 95% confidence interval [CI], 0.56-0.89; P = 0.0037), or with inter-year (4.92 admissions per day; incidence rate ratio, 0.57; 95% confidence interval, 0.45-0.72; P < 0.001). Patients admitted during study period were less frequently admitted in New York Heart Association (NYHA) Class II compared with inter-year period (P = 0.019). At covariance analysis NYHA class was significantly lower in patients admitted during inter-year control period, compared with patients admitted during case period (P = 0.014)., Conclusions: Admissions for HF were significantly reduced during the lockdown due to the COVID-19 pandemic in Italy., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Heart failure is characterized by a tissue damage that progressively leads to mechanical cardiac dysfunction and remodeling. A recent investigation showed that α-1 antitripsin, an antiprotease, able to inhibit metalloproteinases, provides prognostic information about heart failure and mortality postacute myocardial infarction. Therefore, we conducted a study to establish if α-1 antitrypsin (AAT) could be considered a marker of severity of heart failure., Methods: A total of 182 heart failure patients (Group 1) were enrolled and AAT values were compared with controls (Group 2)., Results: In Group 1 a significant increment of AAT levels respect to Group 2 was observed (P < 0.0001). Moreover, in patients enrolled a progressive elevation of AAT levels across New York Heart Association classes (P < 0.0001) was found. Patients with α-1 antitripsin levels above median value showed lower hemoglobin concentration, higher circulating levels of C-reactive protein, hs-troponin T and B-type natriuretic peptide prohormone. Group 1 AAT levels resulted highly positively associated to B-type natriuretic peptide prohormone, C-reactive protein levels, while negatively associated to left ventricular ejection fraction%. However, at multivariate logistic analysis, only C-reactive protein was confirmed in a subgroup of postischemic heart failure patients., Conclusion: Adding AAT levels to the panel of heart failure biomarkers allow a better stratification of patients with heart failure.

Background: Evidence of sympathetic and renin-angiotensin-aldosterone system activation provided a rationale for neurohormonal antagonism in heart failure with reduced ejection fraction (HFrEF), while no data are available in patients with milder degree of systolic dysfunction. We aimed to investigate neurohormonal function in HF with preserved and mid-range EF (HFpEF/HFmrEF)., Methods: Three cohorts (n = 189/each) of stable HFpEF, HFmrEF and HFrEF patients were selected (median age 70, 67 and 67 years; male 56%, 73% and 74%, respectively). Patients received a baseline clinical assessment including plasma renin activity (PRA), aldosterone, catecholamines, and N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP) assays, and were followed-up for all-cause death., Results: Neuroendocrine profile was similar between HFpEF and HFmrEF, while all neurohormones except epinephrine were higher in HFrEF than in HFmrEF (NT-proBNP 2332 ng/L, IQR 995-5666 vs 575 ng/L, 205-1714; PRA 1.7 ng/mL/h, 0.4-5.6 vs 0.6 ng/mL/h, 0.2-2.6; aldosterone 153 ng/L, 85-246 vs 113 ng/L, 72-177; norepinephrine 517 ng/L, 343-844 vs 430 ng/L, 259-624; all p < 0.001, epinephrine 31 ng/L, 10-63 vs 25 ng/L, 10-44; p = 0.319). These findings were unrelated to treatment heterogeneity. Ten percent of HFpEF patients had elevated PRA, aldosterone and norepinephrine vs. 8% in HFmrEF and 21% in HFrEF. During a 5-year follow-up, survival decreased with the number of neurohormones elevated (HFpEF: log-rank 7.8, p = 0.048; HFmrEF: log-rank 11.8, p = 0.008; HFrEF: log-rank 8.1, p = 0.044)., Conclusions: Neurohormonal activation is present only in a subset of patients with HFpEF and HFmrEF, and may hold clinical significance. Neurohormonal antagonism may be useful in selected HFpEF/HFmrEF population., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background A thorough analysis of noncardiac determinants of mortality in heart failure (HF) is missing. Furthermore, evidence conflicts on the outcome of patients with HF and no or mild systolic dysfunction. We aimed to investigate the prevalence of noncardiac and cardiac causes of death in a cohort of chronic HF patients, covering the whole spectrum of systolic function. Methods and Results We enrolled 2791 stable HF patients, classified into HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction [EF] <40%), HR with midrange EF (HFmrEF; left ventricular EF 41-49%), or HF with preserved EF (HFpEF; left ventricular EF ≥50%), and followed up for all-cause, cardiac, and noncardiac mortality (adjudicated as due to cancer, sepsis, respiratory disease, renal disease, or other causes). Over follow-up of 39 months, adjusted mortality was lower in HFpEF and HFmrEF versus HFrEF (hazard ratio: 0.75 [95% CI, 0.67-0.84], P <0.001 for HFpEF; hazard ratio: 0.78 [95% CI, 0.63-0.96], P =0.017 for HFmrEF). HFrEF had the highest rates of cardiac death, whereas noncardiac mortality was similar across left ventricular EF categories. Noncardiac causes accounted for 62% of deaths in HFpEF, 54% in HFmrEF and 35% in HFrEF; cancer was twice as frequent as a cause of death in HFpEF and HFmrEF versus HFrEF. Yearly rates of noncardiac death exceeded those of cardiac death since the beginning of follow-up in HFpEF and HFmrEF. Conclusions Noncardiac death is a major determinant of outcome in stable HF, exceeding cardiac-related mortality in HFpEF and HFmrHF. Comorbidities should be regarded as main therapeutic targets and objects of dedicated quality improvement initiatives, especially in patients with no or mild systolic dysfunction.

Background: Although central apneas (CA) and obstructive apneas (OA) are highly prevalent in heart failure (HF), a comparison of apnea prevalence, predictors and clinical correlates in the whole HF spectrum, including HF with reduced ejection fraction (HFrEF), mid-range EF (HFmrEF) and preserved EF (HFpEF) has never been carried out so far. Materials and methods: 700 HF patients were prospectively enrolled and then divided according to left ventricular EF (408 HFrEF, 117 HFmrEF, 175 HFpEF). All patients underwent a thorough evaluation including: 2D echocardiography; 24-h Holter-ECG monitoring; cardiopulmonary exercise testing; neuro-hormonal assessment and 24-h cardiorespiratory monitoring. Results: In the whole population, prevalence of normal breathing (NB), CA and OA at daytime was 40, 51, and 9%, respectively, while at nighttime 15, 55, and 30%, respectively. When stratified according to left ventricular EF, CA prevalence decreased (daytime: 57 vs. 43 vs. 42%, p = 0.001; nighttime: 66 vs. 48 vs. 34%, p < 0.0001) from HFrEF to HFmrEF and HFpEF, while OA prevalence increased (daytime: 5 vs. 8 vs. 18%, p < 0.0001; nighttime 20 vs. 29 vs. 53%, p < 0.0001). In HFrEF, male gender and body mass index (BMI) were independent predictors of both CA and OA at nighttime, while age, New York Heart Association functional class and diastolic dysfunction of daytime CA. In HFmrEF and HFpEF male gender and systolic pulmonary artery pressure were independent predictors of CA at daytime, while hypertension predicted nighttime OA in HFpEF patients; no predictor of nighttime CA was identified. When compared to patients with NB, those with CA had higher neuro-hormonal activation in all HF subgroups. Moreover, in the HFrEF subgroup, patients with CA were older, more comorbid and with greater hemodynamic impairment while, in the HFmrEF and HFpEF subgroups, they had higher left atrial volumes and more severe diastolic dysfunction, respectively. When compared to patients with NB, those with OA were older and more comorbid independently from background EF. Conclusions: Across the whole spectrum of HF, CA prevalence increases and OA decreases as left ventricular systolic dysfunction progresses. Different predictors and specific clinical characteristics might help to identify patients at risk of developing CA or OA in different HF phenotypes.