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Purpose Clinical practice forces the necessity to conduct a clinical trial concerning the group of outpatients with chronically advanced heart failure in III or IV NYHA functional class, frequently requiring hospitalizations due to HF exacerbation, and often left without any additional therapeutic option. The current trial aims to determine the efficacy and safety of repeated levosimendan infusions in the group of severe outpatients with reduced ejection fraction (HFrEF). Material and methods LEIA-HF (LEvosimendan In Ambulatory Heart Failure Patients) is a multicentre, randomized, double-blind, placebo-controlled, phase 4 clinical trial to determine whether the repetitive use of levosimendan reduces the incidence of adverse cardiovascular events in ambulatory patients with chronic, advanced HFrEF. A total of 350 patients will be randomized in a 1:1 ratio to receive either levosimendan or placebo, which will be administered as continuous 24 ​h infusions, every 4 weeks for 48 weeks (12 infusions in total – phase I), and followed by double-blind 6 visits, every 4 weeks (phase II of the trial including the option of restarting levosimendan or placebo, based on the fulfillment of additional criteria). The primary endpoint for efficacy assessment will be death from any cause or unplanned hospitalization for HF assessed together, whichever occurs first, in a 12-month follow-up period. Conclusions A well-designed study with a consistent protocol, including the drug side effects, comprehensive clinical assessment, appropriate definition of endpoints, and monitoring therapy, may provide a complete overview of the effectiveness and safety profile of the repetitive levosimendan administration in ambulatory severe HFrEF patients.

Cardiomyopathies are mostly determined by genetic mutations affecting either cardiac muscle cell structure or function. Nevertheless, cardiomyopathies may also be part of complex clinical phenotypes in the spectrum of neuromuscular (NMD) or mitochondrial diseases (MD). The aim of this study is to describe the clinical, molecular, and histological characteristics of a consecutive cohort of patients with cardiomyopathy associated with NMDs or MDs referred to a tertiary cardiomyopathy clinic. Consecutive patients with a definitive diagnosis of NMDs and MDs presenting with a cardiomyopathy phenotype were described. Seven patients were identified: two patients with ACAD9 deficiency (Patient 1 carried the c.1240C>T (p.Arg414Cys) homozygous variant in ACAD9; Patient 2 carried the c.1240C>T (p.Arg414Cys) and the c.1646G>A (p.Ar549Gln) variants in ACAD9); two patients with MYH7-related myopathy (Patient 3 carried the c.1325G>A (p.Arg442His) variant in MYH7; Patient 4 carried the c.1357C>T (p.Arg453Cys) variant in MYH7); one patient with desminopathy (Patient 5 carried the c.46C>T (p.Arg16Cys) variant in DES); two patients with mitochondrial myopathy (Patient 6 carried the m.3243A>G variant in MT-TL1; Patient 7 carried the c.253G>A (p.Gly85Arg) and the c.1055C>T (p.Thr352Met) variants in MTO1). All patients underwent a comprehensive cardiovascular and neuromuscular evaluation, including muscle biopsy and genetic testing. This study described the clinical phenotype of rare NMDs and MDs presenting as cardiomyopathies. A multidisciplinary evaluation, combined with genetic testing, plays a main role in the diagnosis of these rare diseases, and provides information about clinical expectations, and guides management.

Cardiac contractility modulation (CCM) is a novel device-based therapy used in patients with HFrEF. CCM therapy is associated with an improvement in exercise tolerance, increased quality of life, reduced HF hospitalizations, and reverse remodelling of the left ventricle in patients with HFrEF. In this case, we report the clinical benefit of CCM in an older patient with advanced HFrEF due to ischemic dilated cardiomyopathy with frequent heart failure-related hospitalizations and poor quality of life despite optimal medical therapy.

Left ventricular assist device implantation is a challenging procedure in the presence of a giant thrombosed aneurysm, and no standard surgical techniques are currently recommended in this setting. In this case, we report the successful implantation of a left ventricular assist device (HeartMate III) in a patient with a massive thrombosed apical aneurysm. The patient presented with extended antero-apical necrosis as a result of a delay in hospital admission for acute coronary syndrome due to the patient’s concerns about the COVID-19 pandemic outbreak.

No data on the add-on sacubitril/valsartan (S/V) therapy among cardiac resynchronization therapy with a defibrillator (CRT-D) nonresponder patients are currently available in literature. We conducted a prospective observational study including 190 CRT-D nonresponder patients with symptomatic heart failure with reduced ejection fraction despite the optimal medical therapy from at least 1 year. The primary endpoint was the rate of additional responders (left ventricular end-systolic volume reduction >15%) at 12 months from the introduction of S/V therapy. At the end of the 12 months follow-up, 37 patients (19.5%) were deemed as "additional responders" to the combination use of CRT + S/V therapy. The only clinical predictor of additional response was a lower left ventricular ejection fraction [OR 0.881 (0.815-0.953), P = 0.002] at baseline. At 12 months follow-up, there were significant improvements in heart failure (HF) symptoms and functional status [New York Heart Association 2 (2-3) vs. 1 (1-2), P < 0.001; physical activity duration/day: 10 (8-12) vs. 13 (10-18) hours, P < 0.001]. Compared with the 12 months preceding S/V introduction, there were significant reductions in the rate of HF rehospitalization (35.5% vs. 19.5%, P < 0.001), in atrial tachycardia/atrial fibrillation burden [6.0 (5.0-8.0) % vs. 0 (0-2.0) %, P < 0.001] and in the proportions of patients experiencing ventricular arrhythmias (21.6% vs. 6.3%; P < 0.001). Our results indicate that S/V add-on therapy in CRT-D nonresponder patients is associated with 19.5% of additional responders, a reduction in HF symptoms and rehospitalizations, AF burden, and ventricular arrhythmias.

Cardiopulmonary exercise testing is a prognostic tool in heart failure with reduced left ventricular ejection fraction (HFrEF). Prognosticating algorithms have been proposed, but none has been validated. In 2017, a predictive algorithm, based on peak oxygen consumption (VO2), ventilatory response to exercise (ventilation [VE] carbon dioxide production [VCO2], the VE/VCO2 slope), exertional oscillatory ventilation (EOV), and peak respiratory exchange ratio, was recommended, according treatment with β blockers: patients with HFrEF registered in the metabolic exercise test data combined with cardiac and kidney indexes (MECKIs) database were used to validated this algorithm. According to the inclusion/exclusion criteria, 4,683 MECKI patients with HFrEF were enrolled. At 3years follow-up, the end point was cardiovascular death and urgent heart transplantation (cardiovascular events [CV]). CV events occurred in 25% in patients without β blockers, whereas those with β-blockers had 11% (p 10

Aims Cardiac contractility modulation therapy (CCMT) has been shown to reduce hospitalizations and to improve quality of life in heart failure patients with reduced ejection fraction (HFrEF) who remain symptomatic despite disease-modifying therapies. Strain imaging derived myocardial work (MW) is an emerging tool for evaluating left ventricular mechanics by incorporating systolic deformation and afterload burden in the analysis. To evaluate prospectively the impact of CCMT in HFrEF patients on MW derived parameters in relation to standard echocardiographic indices. Methods and results We recruited 12 HFrEF patients with indications to CCMT according to current clinical practice. A comprehensive echo-Doppler evaluation, including speckle tracking derived assessment of global longitudinal strain (GLS), was performed before and after three months from the CCM device implantation. Parameters of MW such as global work index (GWI), global constructive work (GCW) global wasted work (GWW), and global work efficiency (GWE) were calculated according to standardized procedures. Median values (interquartile range) were compared for all those parameters from baseline and 3-month follow-up with Wilcoxon Rank Sum test for continuous variables. At three months from CCM implant an improvement of LVEF [from 32% (27–34) to 36% (29–39), P Conclusions At 3 months, CCMT significantly improves standard and advanced left ventricular systolic function indices. This improvement is due to the increase of constructive work and a reduction of wasted work. In addition, the increase of left ventricular ejection fraction can be predicted by the global constructive work levels at baseline.

Aims To evaluate to role of bisoprolol to control symptoms and left ventricular outflow tract obstruction (LVOTO) in a consecutive cohort of adults with hypertrophic cardiomyopathy (HCM). Methods and results In this retrospective study, patients with HCM with an LVOT gradient ≥50mmHg after Valsalva manoeuvre and New York Heart Association (NYHA) class II-III symptoms were assigned to receive bisoprolol (starting at 1.25 mg daily). The initial dose was increased every two weeks to achieve the target in LVOT gradient Conclusions Treatment with bisoprolol was well-tolerated and effective in relieving obstruction and improving symptoms in a significant proportion of patients with symptomatic obstructive HCM.

Aims This study sought to describe the characteristics and the natural course of left ventricular hypertrophy (LVH) in a well-characterized consecutive cohort of infants of diabetic mothers (IDMs). Methods and results Sixty consecutive IDMs with LVH have been retrospectively identified and enrolled in the study. All IDMs were evaluated at baseline and every 6 months until LV wall thickness regression, defined as the decrease of wall thickness measurement into the normal reference range for cardiac parameters (z-score > −2 and Conclusions LVH in IDMs represents a benign condition with complete regression during the first years of life. In those patients without LV wall thickness regression, combined with clinical markers suggesting a specific disease, a complete work-up is required for a definite diagnosis.

The term arrhythmogenic cardiomyopathy (ACM) describes a large spectrum of myocardial diseases characterized by progressive fibrotic or fibrofatty replacement, which gives the substrate for the occurrence of ventricular tachyarrhythmias and the development of ventricular dysfunction. This condition may exclusively affect the left ventricle, leading to the introduction of the term arrhythmogenic left ventricular cardiomyopathy (ALVC). The clinical features of ALVC are progressive fibrotic replacement with the absence or mild dilation of the LV and the occurrence of ventricular arrhythmias within the left ventricle. In 2019, the diagnostic criteria for the diagnosis of ALVC, based on family history and clinical, electrocardiographic, and imaging features, have been proposed. However, since the significant clinical and imaging overlap with other cardiac diseases, genetic testing with the demonstration of a pathogenic variant in an ACM-related gene is required for diagnostic confirmation. In ALVC, the multimodality imaging approach comprises different imaging techniques, such as echocardiography, cardiac magnetic resonance, and cardiac nuclear imaging. It provides essential information for the diagnosis, differential diagnosis, sudden cardiac death risk stratification, and management purposes. This review aims to elucidate the current role of the different multimodality imaging techniques in patients with ALVC.

Introduction: We sought to determine prevalence and predictive accuracy of clinical markers (red flags, RF), known to be associated with specific systemic disease in a consecutive cohort of patients with hypertrophic cardiomyopathy (HCM). Methods: We studied 129 consecutive patients (23.7 ± 20.9 years, range 0–74 years; male/female 68%/32%). Pre-specified RF were categorized into five domains: family history; signs/symptoms; electrocardiography; imaging; and laboratory. Sensitivity (Se), specificity (Sp), negative predictive value (NPV), positive predictive value (PPV), and predictive accuracy of RF were analyzed in the genotyped population. Results: In the overall cohort of 129 patients, 169 RF were identified in 62 patients (48%). Prevalence of RF was higher in infants (78%) and in adults >55 years old (58%). Following targeted genetic and clinical evaluation, 94 patients (74%) had a definite diagnosis (sarcomeric HCM or specific causes of HCM). We observed 14 RF in 13 patients (21%) with sarcomeric gene disease, 129 RF in 34 patients (97%) with other specific causes of HCM, and 26 RF in 15 patients (45%) with idiopathic HCM (p < 0.0001). Non-sarcomeric causes of HCM were the most prevalent in ages 55yo. Se, Sp, PPV, NPV and PA of RF were 97%, 70%, 55%, 98% and 77%, respectively. Single and clinical combination of RF (clusters) had an high specificity, NPV and predictive accuracy for the specific etiologies (syndromes/metabolic/infiltrative disorders associated with HCM). Conclusions: An extensive diagnostic work up, focused on analysis of specific diagnostic RF in patients with unexplained LVH facilitates a clinical diagnosis in 74% of patients with HCM.

Aims: Exercise oscillatory ventilation (EOV) is a pivotal cardiopulmonary exercise test parameter for the prognostic evaluation of patients with chronic heart failure (HF). It has been described in patients with HF with reduced ejection fraction (50%, HFpEF), but no data are available for patients with HF with mid-range ejection fraction (40–49%, HFmrEF). The aim of the study was to evaluate the prognostic role of EOV in HFmrEF patients. Methods and results: We analysed 1239 patients with HFmrEF and 4482 patients with HFrEF, enrolled in the MECKI score database, with a 2-year follow-up. The study endpoint was the composite of cardiovascular death, urgent heart transplant, and ventricular assist device implantation. We identified EOV in 968 cases (16% and 17% of cases in HFmrEF and HFrEF,. respectively). HFrEF EOV+ patients were significantly older, and their parameters suggested a more severe HF than HFrEF EOV− patients. A similar behaviour was found in HFmrEF EOV+ vs. EOV− patients. Kaplan–Meier analysis, irrespective of ejection fraction, showed that EOV is associated with a worse survival, and that patients with HFrEF and HFmrEF EOV+ had a significantly worse outcome than the EOV− of the same ejection fraction groups. EOV-associated survival differences in HFmrEF patients started after 18 months of follow-up. Conclusion: Exercise oscillatory ventilation has a similar prevalence and ominous prognostic value in both HFmrEF and HFrEF patients, indicating a group of patients in need of a more intensive follow-up and a more aggressive therapy. In HFmrEF, the survival curves between EOV+ and EOV− patients diverged only after 18 months.

Levosimendan is an inodilator drug that, given its unique pharmacological actions and safety profile, represents a viable therapeutic option in patients with heart failure with reduced ejection fraction in the advanced stage of the disease (advHFrEF). Pulsed levosimendan infusion in patients with advHFrEF improves symptoms and clinical and hemodynamic status, prevents recurrent hospitalizations, and enables optimization of guidelines-directed medical therapy. Furthermore, considering its proprieties on right ventricular function and pulmonary circulation, levosimendan could be helpful for the prevention and treatment of the right ventricular dysfunction post-implanting a left ventricular assist device. However, to date, evidence on this issue is scarce and has yielded mixed results. Finally, preliminary experiences indicate that treatment with levosimendan at scheduled intervals may serve as a “bridge to transplant” strategy in patients with advHFrEF. In this review, we summarized the clinical pharmacology of levosimendan, the available evidence in the treatment of patients with advHFrEF, as well as a hypothesis for its use in patients with advanced heart failure with preserved ejection fraction.

Background: Virtually all patients with heart failure with reduced ejection fraction have a reduction of myocardial mechano-energetic efficiency (MEE). Cardiac contractility modulation (CCM) is a novel therapy for the treatment of patients with HFrEF, in whom it improves the quality of life and functional capacity, reduces hospitalizations, and induces biventricular reverse remodeling. However, the effects of CCM on MEE and global longitudinal strain (GLS) are still unknown; therefore, this study aims to evaluate whether CCM therapy can improve the MEE of patients with HFrEF. Methods: We enrolled 25 patients with HFrEF who received an Optimizer Smart implant (the device that develops CCM therapy) between January 2018 and January 2021. Clinical and echocardiographic evaluations were performed in all patients 24 h before and six months after CCM therapy. Results: At six months, follow-up patients who underwent CCM therapy showed an increase of left ventricular ejection fraction (30.8 ± 7.1 vs. 36.1 ± 6.9%; p = 0.032) as well a rise of GLS 10.3 ± 2.7 vs. −12.9 ± 4.2; p = 0.018), of MEE (32.2 ± 10.1 vs. 38.6 ± 7.6 mL/s; p = 0.013) and of MEE index (18.4 ± 6.3 vs. 24.3 ± 6.7 mL/s/g; p = 0.022). Conclusions: CCM therapy increased left ventricular performance, improving left ventricular ejection fraction, GLS, as well as MEE and MEEi.

Treatment with β-blockers is the main strategy for managing patients with heart failure and reduced ejection fraction because of their ability to reverse the neurohumoral effects of the sympathetic nervous system, with consequent prognostic and symptomatic benefits. However, to date, they are underused, mainly because of the misconception that hypotension and bradycardia may worsen the haemodynamic status of patients with HFrEF and because of the presence of comorbidities falsely believed to be absolute contraindications to their use. To promote proper use of β-blockers in this article, we review the clinical pharmacology of β-blockers, the evidence of the beneficial effects of these drugs in heart failure with reduced ejection fraction, and the current guidelines for their use in clinical practice and in the presence of comorbidities (e.g., pulmonary disease, diabetes, atrial fibrillation, peripheral arterial disease, etc.). It is hoped that the practical approach discussed in this review will allow for a proper diffusion of knowledge about the correct use of β-blockers and the drug-disease interactions to achieve their increased use and titration, as well as for the selection of a specific agent with a view to a properly tailored approach for HFrEF patients.

Background: Patients with advanced heart failure with reduced ejection fraction often cannot tolerate target doses of guideline-directed medical therapy due to symptomatic hypotension, renal dysfunction, and associated electrolyte abnormalities. While levosimendan can facilitate the titration of β-blockers in patients with advanced HFrEF, it is unclear whether ambulatory levosimendan infusions would offer the same benefit. In this prospective study, we investigate the effects of intermittent ambulatory levosimendan infusions on the uptitration of disease-modifying drugs. Methods: We enrolled 37 patients with advanced HFrEF who received repeated ambulatory infusions of levosimendan between January 2018 and January 2021. The demographic, clinical, and laboratory data were acquired 24 h before the first and the last ambulatory levosimendan infusion. Results: At the 1 year follow-up, the enrolled patients were on significantly higher doses of guideline-directed medical therapy, including bisoprolol (3.2 ± 2.8 mg vs. 5.9 ± 4.1 mg; p = 0.02), sacubitril/valsartan (41.67 ± 32.48 mg vs. 68.5 ± 35.72 mg; p = 0.01), and eplerenone (12.7 ± 8.5 mg vs. 22.8 ± 13.6 mg; p = 0.03). Furthermore, a substantial decrease in the furosemide dose was observed (123.2 ± 32.48 mg vs. 81.6 ± 19.47 mg; p < 0.0001). Conclusions: Levosimendan facilitates the optimization of disease-modifying heart failure medications in previously intolerant advanced HFrEF patients.

Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by left ventricular hypertrophy not solely explained by abnormal loading conditions. Despite its rare prevalence in pediatric age, HCM carries a relevant risk of mortality and morbidity in both infants and children. Pediatric HCM is a large heterogeneous group of disorders. Other than mutations in sarcomeric genes, which represent the most important cause of HCM in adults, childhood HCM includes a high prevalence of non-sarcomeric causes, including inherited errors of metabolism (i.e., glycogen storage diseases, lysosomal storage diseases, and fatty acid oxidation disorders), malformation syndromes, neuromuscular diseases, and mitochondrial disease, which globally represent up to 35% of children with HCM. The age of presentation and the underlying etiology significantly impact the prognosis of children with HCM. Moreover, in recent years, different targeted approaches for non-sarcomeric etiologies of HCM have emerged. Therefore, the etiological diagnosis is a fundamental step in designing specific management and therapy in these subjects. The present review aims to provide an overview of the non-sarcomeric causes of HCM in children, focusing on the pathophysiology, clinical features, diagnosis, and treatment of these rare disorders.

Introduction: Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy and a common cause of heart failure with preserved and mid-range ejection fraction (HFpEF and HFmrEF). Left ventricular (LV) systolic assessment is pivotal in differential diagnostic and prognostic stratification in CA. However, nondeformation and deformation-based parameters classically implied had many limitations. Myocardial work (MW) has been recently introduced for the evaluation of myocardial performance, in a load-independent fashion, in patients with cardiomyopathies. Aims: This study aimed to evaluate MW parameters in LV performance assessment in CA and their possible role in differential diagnosis between AL and ATTR forms, compared with other echocardiographic parameters, also exploring the possible association between MW parameters and blood biomarkers. Materials and Methods: The study population consisted of 25 patients with CA (10 with AL amyloidosis and 15 with wild-type ATTR [ATTRwt] form) and HFpEF or HFmrHF, enrolled between March 2018 and December 2019, undergoing a comprehensive clinical, biochemical, and imaging evaluation. Ten healthy individuals were studied as controls. ATTR patients had a noninvasive diagnosis of wtATTR-CA (positive 99m Tc-hydroxy methylene-diphosphonate scintigraphy with a negative hematological screening), while AL patients underwent endomyocardial biopsy. All patients underwent standard transthoracic echocardiography. MW and related indices were estimated using a vendor-specific module. Results: Compared to the ATTRwt group, patients in the AL group showed a more pronounced myocardial performance impairment assessed by Global Word Efficiency (GWE: 83.5% ± 6.3% vs. 88.2% ± 3.6%; P = 0.026). In multiple linear regression analysis, cardiac troponin I (B =-0.55; P < 0.0001), global longitudinal strain (B =0.35; P < 0.008), and regional relative strain ratio (B =-0.30; P < 0.016) were significant predictors of GWE reduction in CA patients. At receiver operating characteristics curve analysis, among all other deformation-based and nondeformation-based echocardiographic parameters, GWE showed the highest area under the curve (AUC) (AUC 0.74; 95% CI: 0.55-0.96; P < 0.04). The optimal cutoff was determined by sensitivity/specificity analysis: A GWE < 86.5% identified patients with AL amyloidosis with a sensitivity and specificity, respectively, of 80.0% and 66.7%. Conclusions: The results of our pivotal study seem to highlight the importance of new deformation parameters to study myocardial performance in patients with CA, and to differentiate between AL CA and ATTR CA.

Funding Acknowledgements Type of funding sources: None. Background Intermittent infusions of levosimendan in an outpatient setting have been associated with improved symptoms and reduced hospitalizations in patients with advanced heart failure (HF). Little is known on the potential effect of intermittent levosimendan infusions on right ventricle (RV)-pulmonary arterial (PA) coupling in ambulatory patients with advanced HF. Purpose Aim of the present study was to explore the effects of intermittent levosimendan infusions on the ratio between tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PAPs), an echocardiographic measure of RV/PA coupling, in ambulatory patients with advanced HF, and on left ventricular arterial coupling (VAC), expressed as the relationship between arterial elastance (Ea) and ventricular elastance (Ees). Methods 17 ambulatory patients with advanced HF treated with intermittent levosimendan (6-hour intravenous infusion, 0.2 ug/kg/min without bolus) received baseline clinical, biochemical and echocardiographic evaluation and changes in TAPSE/PAPs ratio were assessed from baseline to 48 hours after the infusion, based on the pharmacokinetic profile of levosimendan. VAC, expressed as Ea/Ees ratio, was obtained by a calculator (iElastance) designed for non-invasive single beat measure of end-systolic Ees and Ea according to Chen"s method. Results After 48 hours from levosimendan infusion, there was a significant improvement of TAPSE/PAPs ratio (p = 0.04), stroke voume (SV) (p = 0.05) and cardiac output (CO)(p = 0.04). We observed a significant reduction of Ea (p = 0.007) and of Ees (p = 0.01) and a non significant improvement of VAC (p = 0.4)(Tab.1). Conclusion. Our results show that an intermittent 6-hour levosimendan infusion at 0.2 ug/kg/min improves after 48 hours RV-PA coupling, SV, CO, Ea and Ees in ambulatory patients with advanced HF. Further studies including more patients are necessary to confirm these preliminary findings. Tab.1 Baseline 48h afterlevosimendan infusion p value NT-proBNP (pg/mL) 5607 ± 4300 3868 ± 3856

Cardiomyopathies (CMPs) represent a diverse group of heart muscle diseases, grouped into specific morphological and functional phenotypes. CMPs are associated with mutations in sarcomeric and non-sarcomeric genes, with several suspected epigenetic and environmental mechanisms involved in determining penetrance and expressivity. The understanding of the underlying molecular mechanisms of myocardial diseases is fundamental to achieving a proper management and treatment of these disorders. Among these, inflammation seems to play an important role in the pathogenesis of CMPs. The aim of the present study is to review the current knowledge on the role of inflammation and the immune system activation in the pathogenesis of CMPs and to identify potential molecular targets for a tailored anti-inflammatory treatment.

In this report, an atypical case of Noonan syndrome (NS) associated with sarcomeric hypertrophic cardiomyopathy (HCM) in a 33-year-old patient was described. Genetic testing revealed two different disease-causing mutations: a mutation in the PTPN11 gene, explaining NS, and a mutation in the MYBPC3 gene, known to be associated with HCM. This case exemplifies the challenge in achieving a definite etiological diagnosis in patients with HCM and the need to exclude other diseases mimicking this condition (genocopies or phenocopies). Compound heterozygous mutations are rare but possible in HCM patients. In conclusion, this study highlights the important role of genetic testing as a necessary diagnostic tool for performing a definitive etiological diagnosis of HCM.

Aims: Exercise-derived parameters, specifically peak exercise oxygen uptake (peak VO2) and minute ventilation/carbon dioxide relationship slope (VE/VCO2 slope), have a pivotal prognostic value in heart failure (HF). It is unknown how the prognostic threshold of peak VO2 and VE/VCO2 slope has changed over the last 20 years in parallel with HF prognosis improvement. Methods and results: Data from 6083 HF patients (81% male, age 61 ± 13 years), enrolled in the MECKI score database between 1993 and 2015, were retrospectively analysed. By enrolment year, four groups were generated: group 1 1993–2000 (n = 440), group 2 2001–2005 (n = 1288), group 3 2006–2010 (n = 2368), and group 4 2011–2015 (n = 1987). We compared the 10-year survival of groups and analysed how the overall risk (cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation) changed over time according to peak VO2 and VE/VCO2 slope and to major clinical and therapeutic variables. At 10 years, a progressively higher survival from group 1 to group 3 was observed, with no further improvement afterwards. A 20% risk for peak VO2 15 mL/min/kg (95% confidence interval 16–13), 9 (11–8), 4 (4–2) and 5 (7–4) was observed in group 1, 2, 3, and 4, respectively, while the VE/VCO2 slope value for a 20% risk was 32 (37–29), 47 (51–43), 59 (64–55), and 57 (63–52), respectively. Conclusions: Heart failure prognosis improved over time up to 2010 in a HF population followed by experienced centres. The peak VO2 and VE/VCO2 slope cut-offs identifying a definite risk progressively decreased and increased over time, respectively. The prognostic threshold of peak VO2 and VE/VCO2 slope must be updated whenever HF prognosis improves.

The usefulness of β-blockers in heart failure (HF) patients with permanent atrial fibrillation (AF) has been questioned. Background: The usefulness of β-blockers in heart failure (HF) patients with permanent atrial fibrillation (AF) has been questioned. Methods and results: We analyzed data from HF patients (958 patients (801 males, 84%, age 67 ± 11 years)) with AF enrolled in the MECKI score database. We evaluated prognosis (composite of cardiovascular death, urgent heart transplant, or left ventricular assist device) of patients receiving β-blockers (n = 777, 81%) vs. those not treated with β-blockers (n = 181, 19%). We also analyzed the role β1-selectivity and the role of daily β-blocker dose. To account for different HF severity, Kaplan-Meier survival curves were normalized for relevant confounding factors and for treatment strategies. Dose was available in 629 patients. Median follow-up was 1312 (577–2304) days in the entire population, 1203 (614–2420) and 1325 (569–2300) days in patients not receiving and receiving β-blockers. 224 (23%, 54/1000 events/year), 163 (21%, 79/1000 events/year), and 61 (34%, 49/1000 events/year) events were recorded, respectively. At 10-year patients treated with β-blockers had a better outcome (HR 0.447, p < 0.01) with no effects as regards β1selective drugs (53%) vs. β1-β2 blockers (47%). Survival improved in parallel with β-blocker dose increase (HR 0.296, 0.496, 0.490 for the high, medium, and low dose vs. no β-blockers, p < 0.0001). Conclusion: HF patients with AF taking a β-blocker have a better outcome (with a survival improvement in parallel with daily dose but no differences as regards β1 selectivity) but this does not mean that β-blockers improve outcomes in these patients as we cannot control for all the potential confounders associated with β-blocker use.