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Mineralocorticoid receptor antagonists (MRAs) reduce hospitalisations and death in patients with heart failure and reduced ejection fraction (HFrEF), but the benefit in patients with heart failure and mildly reduced ejection fraction (HFmrEF) or heart failure and preserved ejection fraction (HFpEF) is unclear. We evaluated the effect of MRAs in four trials that enrolled patients with heart failure across the range of ejection fraction. This is a prespecified, individual patient level meta-analysis of the RALES (spironolactone) and EMPHASIS-HF (eplerenone) trials, which enrolled patients with HFrEF, and of the TOPCAT (spironolactone) and FINEARTS-HF (finerenone) trials, which enrolled patients with HFmrEF or HFpEF. The primary outcome of this meta-analysis was a composite of time to first hospitalisation for heart failure or cardiovascular death. We also estimated the effect of MRAs on components of this composite, total (first or repeat) heart failure hospitalisations (with and without cardiovascular deaths), and all-cause death. Safety outcomes were also assessed, including serum creatinine, estimated glomerular filtration rate, serum potassium, and systolic blood pressure. An interaction between trials and treatment was tested to examine the heterogeneity of effect in these populations. This study is registered with PROSPERO, CRD42024541487. 13 846 patients were included in the four trials. MRAs reduced the risk of cardiovascular death or heart failure hospitalisation (hazard ratio 0·77 [95% CI 0·72–0·83]). There was a statistically significant interaction by trials and treatment (p for interaction=0·0012) due to the greater efficacy in HFrEF (0·66 [0·59–0·73]) compared with HFmrEF or HFpEF (0·87 [0·79–0·95]). We observed significant reductions in heart failure hospitalisation in the HFrEF trials (0·63 [0·55–0·72]) and the HFmrEF or HFpEF trials (0·82 [0·74–0·91]). The same pattern was observed for total heart failure hospitalisations with or without cardiovascular death. Cardiovascular death was reduced in the HFrEF trials (0·72 [0·63–0·82]) but not in the HFmrEF or HFpEF trials (0·92 [0·80–1·05]). All-cause death was also reduced in the HFrEF trials (0·73 [0·65–0·83]) but not in the HFmrEF or HFpEF trials (0·94 [0·85–1·03]). With an MRA, the risk of hyperkalaemia was doubled compared with placebo (odds ratio 2·27 [95% CI 2·02–2·56]), but the incidence of serious hyperkalaemia (serum potassium >6·0 mmol/L) was low (2·9% vs 1·4%); the risk of hypokalaemia (potassium <3·5 mmol/L) was halved (0·51 [0·45–0·57]; 7% vs 14%). Steroidal MRAs reduce the risk of cardiovascular death or heart failure hospitalisation in patients with HFrEF and non-steroidal MRAs reduce this risk in patients with HFmrEF or HFpEF. None.

In recent years, several studies have shown the usefulness and clinical relevance of left ventricular global longitudinal systolic strain (GLS) in different cardiovascular diseases. In line with this, the role of GLS in patients with heart failure with preserved ejection fraction (HFpEF) has achieved great importance in this predominant form of heart failure in the last years. In this regard, GLS has shown to be not only a sensitive parameter to detect subtle myocardial abnormalities but also a parameter of clinical and prognostic relevance in patients with HFpEF. In this review, we analyze the current evidence concerning the clinical relevance of GLS in patients with HFpEF and we discuss the potential usefulness of GLS in this complex and heterogeneous condition for which so far no effective therapy exists.

BackgroundAlthough treatment options for heart failure (HF) have improved, advanced HF (AdHF) remains a challenging condition, impacting over 10% of patients with a poor prognosis. In severe cases, patients may experience resistance to or intolerance of conventional therapies, leading to frequent hospitalisations and a heightened risk of death. Vericiguat, a novel treatment for HF with reduced ejection fraction (HFrEF), has shown promise in improving outcomes for patients with worsening HF. The VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial demonstrated that vericiguat can reduce the risk of adverse events in patients with EF<45% following a worsening HF event. However, its safety and efficacy in AdHF patients previously receiving chronic levosimendan infusions remain unclear.Methods and resultsIn this prospective study, we evaluated the safety and tolerability of vericiguat in AdHF patients treated with monthly levosimendan infusions at our clinic. Among 18 patients, 8 were eligible for vericiguat, which was associated with better echocardiographic findings, improved quality of life and lower 1-year mortality compared with non-eligible patients. However, 37.5% of patients discontinued the drug due to symptomatic hypotension, highlighting a key challenge in managing this fragile population. Despite this, vericiguat was generally well-tolerated, and no severe adverse effects were observed.DiscussionThis study provides the first prospective evidence supporting the safe use of vericiguat in AdHF patients on chronic levosimendan. However, careful monitoring for hypotension is essential, and titration may be more difficult in this population. Further research is needed to optimise treatment strategies for these high-risk patients.

BackgroundPulmonary embolism (PE) has been described in coronavirus disease 2019 (COVID-19) critically ill patients, but the evidence from more heterogeneous cohorts is limited.MethodsData were retrospectively obtained from consecutive COVID-19 patients admitted to 13 Cardiology Units in Italy, from March 1st to April 9th, 2020, and followed until in-hospital death, discharge, or April 23rd, 2020. The association of baseline variables with computed tomography-confirmed PE was investigated by Cox hazards regression analysis. The relationship between d-dimer levels and PE incidence was evaluated using restricted cubic splines models.ResultsThe study included 689 patients (67.3 ± 13.2 year-old, 69.4% males), of whom 43.6% were non-invasively ventilated and 15.8% invasively. 52 (7.5%) had PE over 15 (9–24) days of follow-up. Compared with those without PE, these subjects had younger age, higher BMI, less often heart failure and chronic kidney disease, more severe cardio-pulmonary involvement, and higher admission d-dimer [4344 (1099–15,118) vs. 818.5 (417–1460) ng/mL, p < 0.001]. They also received more frequently darunavir/ritonavir, tocilizumab and ventilation support. Furthermore, they faced more bleeding episodes requiring transfusion (15.6% vs. 5.1%, p < 0.001) and non-significantly higher in-hospital mortality (34.6% vs. 22.9%, p = 0.06). In multivariate regression, only d-dimer was associated with PE (HR 1.72, 95% CI 1.13–2.62; p = 0.01). The relation between d-dimer concentrations and PE incidence was linear, without inflection point. Only two subjects had a baseline d-dimer < 500 ng/mL.ConclusionsPE occurs in a sizable proportion of hospitalized COVID-19 patients. The implications of bleeding events and the role of d-dimer in this population need to be clarified.Graphic abstract

The remarkable scientific progress in the treatment of patients with heart failure (HF) and reduced ejection fraction (HFrEF) has more than halved the risk of sudden cardiac death (SCD) in this setting. However, SCD remains one of the major causes of death in this patient population. Beyond the acknowledged role of beta blockers and inhibitors of the renin-angiotensin-aldosterone system (RAAS), a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNI), proved to reduce the overall cardiovascular mortality and, more specifically, the risk of SCD in HFrEF patients. The mechanism by which ARNI may reduce the mortality connected with harmful ventricular arrhythmias is not utterly clear. A variety of direct and indirect mechanisms have been suggested, but a favorable left ventricular reverse remodeling seems to play a key role in this setting. Furthermore, the well-known protective effect of implantable cardioverter-defibrillator (ICD) has been debated in HFrEF patients with non-ischemic cardiomyopathy (NICM) arguing against the role of primary prevention ICD in this setting, particularly when ARNI therapy is considered. The purpose of this review was to provide insights into the SCD mechanisms involved in HFrEF patients together with the current role of electrical therapies and new drug agents in this setting.

Aims Treatment response to vericiguat, based on baseline N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) subgroups specified in the protocol, was evaluated in the heart failure (HF) VICTORIA trial population by post hoc analysis of combined lower three quartiles [Q1–Q3] vs. the upper quartile [Q4]. Methods and results VICTORIA participants with available baseline NT‐proBNP levels (n = 4805; 95.1% of total) were included. Compared with patients in Q1–Q3 (NT‐proBNP: Q1, ≤1556 pg/mL; Q2, >1556–2816 pg/mL; and Q3, >2816–5314 pg/mL), patients in Q4 (NT‐proBNP: >5314 pg/mL) were older (69.2 ± 12.0 vs. 66.6 ± 12.1 years), had lower mean ejection fraction (27.2 ± 8.3% vs. 29.5 ± 8.2%; P < 0.0001), and were more likely to be in New York Heart Association (NYHA) Class III (51.8 vs. 35.6%) or IV (2.4 vs. 1.0%). Compared with Q1–Q3, patients in Q4 had higher mean Meta‐Analysis Global Group in Chronic Heart Failure risk score (27.3 ± 6.6 vs. 23.5 ± 6.4; P < 0.0001), had lower mean estimated glomerular filtration rate (eGFR; 51.5 ± 25.5 vs. 65.0 ± 26.8 mL/min/1.73 m2; P < 0.0001) and haemoglobin (12.8 ± 2.0 vs. 13.6 ± 1.9 g/dL; P < 0.0001), and more had atrial fibrillation (48.7% vs. 43.1%; P = 0.0007) and were randomized while hospitalized for HF (14.8 vs. 9.9%; P < 0.0001). Target dose was achieved in 72.3 and 63.7% of patients in Q1–Q3 and Q4, respectively (P < 0.0001). Primary outcome (composite of time to cardiovascular death or first HF hospitalization) rates were 24.5 and 31.7 per 100 patient‐years for vericiguat and placebo in Q1–Q3 [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.69–0.88, P < 0.001] and 73.6 and 63.6 in Q4 (HR 1.15; 95% CI 0.99–1.34, P = 0.070). Serious adverse events were more frequent in NT‐proBNP Q4 (total population) compared with Q1–Q3 (38.3 vs. 32.3%; P = 0.0001), driven mainly by the placebo group. Adverse events leading to death were more frequent in Q4 than Q1–Q3 (5.8 vs. 2.4%; P < 0.0001). Conclusions Plasma NT‐proBNP may help identify patients with worsening HF with reduced ejection fraction, in whom the beneficial effects of vericiguat may be highest. Patients with highest NT‐proBNP values are probably too far advanced, suffering more co‐morbidities, or still clinically unstable after decompensation to derive benefit from vericiguat.

Background Gender-related factors might affect vulnerability to Covid-19. The aim of this study was to describe the role of gender on clinical features and 28-day mortality in Covid-19 patients. Methods Observational study of Covid-19 patients hospitalized in Bergamo, Italy, during the first three weeks of the outbreak. Medical records, clinical, radiological and laboratory findings upon admission and treatment have been collected. Primary outcome was 28-day mortality since hospitalization. Results 431 consecutive adult patients were admitted. Female patients were 119 (27.6%) with a mean age of 67.0 ± 14.5 years (vs 67.8 ± 12.5 for males, p  = 0.54). Previous history of myocardial infarction, vasculopathy and former smoking habits were more common for males. At the time of admission PaO 2 /FiO 2 was similar between men and women (228 [IQR, 134–273] vs 238 mmHg [150–281], p  = 0.28). Continuous Positive Airway Pressure (CPAP) assistance was needed in the first 24 h more frequently in male patients (25.7% vs 13.0%; p  = 0.006). Overall 28-day mortality was 26.1% in women and 38.1% in men ( p  = 0.018). Gender did not result an independent predictor of death once the parameters related to disease severity at presentation were included in the multivariable analysis ( p  = 0.898). Accordingly, the Kaplan–Meier survival analysis in female and male patients requiring CPAP or non-invasive ventilation in the first 24 h did not find a significant difference ( p  = 0.687). Conclusion Hospitalized women are less likely to die from Covid-19; however, once severe disease occurs, the risk of dying is similar to men. Further studies are needed to better investigate the role of gender in clinical course and outcome of Covid-19.

AimsCardiopulmonary exercise testing (CPET) parameters are used for heart failure (HF) prognostication. While the ventilation to carbon dioxide production (VE/VCO2) slope ≥34 identifies high risk, patients with intermediate values remain heterogeneous. The VE/VCO2 Y-intercept, reflecting dead space ventilation at rest and its changes during effort, may refine prognostication.MethodsWe retrospectively analysed 2642 HF. Follow-up was 26 (9–63) months. The study endpoint was the composite of all-cause death, urgent transplant or left ventricular assist device implantation.ResultsMedian age was 62 (53–70) years and left ventricular ejection fraction (LVEF) 33% (27%–39%). 27% of patients were New York Heart Association class III–IV. During follow-up, 534 events occurred. Both VE/VCO₂ slope and peakVO₂ were associated with outcome in univariable and multivariable models (HR 1.04, 95% CI 1.03 to 1.06; HR 0.90, 95% CI 0.88 to 0.93, p<0.001, respectively). Y-intercept was not prognostic univariately but added independent value in multivariable models (HR 1.08, 95% CI 1.04 to 1.13, p<0.001). Prognosis and clinical profiles improved from group A (VE/VCO2 slope ≥34, n=858) to B (28–34, n=943) to C (<28, n=841). Group A versus C patients had lower LVEF (30% (25%–36%) vs 35% (30%–40%), ptrend<0.001), peakVO₂ (12.7 (10.06–15.3) vs 17.7 (14.6–21.6) mL/kg/min, ptrend<0.001) and higher N-terminal pro-B-type natriuretic peptide (1400 (572–3122) vs 454 (174–1081) pg/mL, ptrend<0.001). Only within group B, a high median Y-intercept (B1≥3.9 L/m) clearly identified patients with higher HF severity and worse survival than B2 (<3.9 L/m, log-rank p<0.001).ConclusionAn increase in the VE/VCO2 slope is associated with a progressive lower survival. Y-intercept enhances risk assessment in HF with intermediate VE/VCO₂ slope values.

Validated tools for predicting individual in-hospital mortality of COVID-19 are lacking. We aimed to develop and to validate a simple clinical prediction rule for early identification of in-hospital mortality of patients with COVID-19. We enrolled 2191 consecutive hospitalized patients with COVID-19 from three Italian dedicated units (derivation cohort: 1810 consecutive patients from Bergamo and Pavia units; validation cohort: 381 consecutive patients from Rome unit). The outcome was in-hospital mortality. Fine and Gray competing risks multivariate model (with discharge as a competing event) was used to develop a prediction rule for in-hospital mortality. Discrimination and calibration were assessed by the area under the receiver operating characteristic curve (AUC) and by Brier score in both the derivation and validation cohorts. Seven variables were independent risk factors for in-hospital mortality: age (Hazard Ratio [HR] 1.08, 95% Confidence Interval [CI] 1.07-1.09), male sex (HR 1.62, 95%CI 1.30-2.00), duration of symptoms before hospital admission <10 days (HR 1.72, 95%CI 1.39-2.12), diabetes (HR 1.21, 95%CI 1.02-1.45), coronary heart disease (HR 1.40 95% CI 1.09-1.80), chronic liver disease (HR 1.78, 95%CI 1.16-2.72), and lactate dehydrogenase levels at admission (HR 1.0003, 95%CI 1.0002-1.0005). The AUC was 0.822 (95%CI 0.722-0.922) in the derivation cohort and 0.820 (95%CI 0.724-0.920) in the validation cohort with good calibration. The prediction rule is freely available as a web-app (COVID-CALC: https://sites.google.com/community.unipa.it/covid-19riskpredictions/c19-rp). A validated simple clinical prediction rule can promptly and accurately assess the risk for in-hospital mortality, improving triage and the management of patients with COVID-19.

Heart failure (HF) is a chronic syndrome that is associated with frequent rehospitalization. Patient-focused research suggests that increased health-management activation may lead to favorable clinical outcomes. This article introduces a case study of the development of a patient education and activation tool for use by HF-specialist clinicians, “ENGAGE in HF,” and advocates for wider adoption of co-creation involving people living with HF. Following a behavioral assessment of unmet needs in the HF-patient population in scientific literature, people living with HF were invited to comment on the content plan and excerpts from the tool. Afterwards, HF-specialist clinicians provided their scientific perspective and assessed the content's practical utility. The co-created tool aims to improve dialogue between clinicians and patients. It allows clinicians to personalize conversations, considering each patient's capacity to integrate information and their readiness to engage in shared decision making. Feedback from initial dissemination of the ENGAGE in HF tool among cardiologists in China suggests that use of such tools may lead to improvements in patient education, symptom management, and adherence to medication.