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BackgroundMyeloperoxidase (MPO), a neutrophil-derived enzyme, is associated with oxidative stress and inflammation, which contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Bioactive MPO causes vascular dysfunction and accumulation of serum uric acid (SUA). We investigated the association of plasma MPO and SUA with echocardiographic variables in a populational setting.MethodsThis was a cross-sectional analysis of the fourth visit of the STANISLAS cohort (N=1677 participants, age 49±14 years, 48% male), a population of initially healthy individuals. Participants were divided into four groups according to median plasma MPO and SUA levels. Adjusted linear regression models were used to assess the relationship of plasma MPO and SUA with echocardiographic markers.ResultsParticipants with high MPO and high SUA were older, had more diabetes, a higher body mass index, lower estimated glomerular filtration rate and higher systolic blood pressure. In multivariable regression analyses, compared with patients with low MPO and low SUA, they had decreased left atrial reservoir strain (mean±SE=−1.43±0.62, p=0.022), decreased mitral annular e’ velocity (mean±SE=−0.60±0.16, p<0.001) and more impaired left ventricular systolic global longitudinal strain (mean±SE=0.50±0.23, p=0.029). In contrast, high MPO with low SUA was not associated with impaired diastolic function.ConclusionsIn a population setting, high MPO and SUA, indicative of high bioactive MPO, were associated with early markers of diastolic dysfunction, suggesting a potential role of the MPO pathway in the early development of HFpEF.

BackgroundDiagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging, particularly in older adults. While the Heart Failure Association (HFA)-PEFF and H2FPEF Scores offer structured diagnostic approaches, their clinical utility is still debated. This study aims to compare the diagnostic accuracy of HFpEF Scores versus inclusion criteria used in sodium-glucose cotransporter-2 inhibitors (SGLT2i) trials, age-adjusted N-terminal pro B-type natriuretic peptide (NT-proBNP) thresholds and the universal definition of heart failure (HF).MethodsDiagnostic tools were assessed using sex-weighted and age-weighted propensity score adjustment in individuals aged 60–80 years from two established HFpEF cohorts (MEtabolic Road to DIAstolic Heart Failure (MEDIA), n=297; Karolinska-Rennes (KaRen), n=174) and two community-based cohorts without HF (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS), n=461; Malmö, n=1030).ResultsHFA-PEFF and H2FPEF Scores classified a large proportion of participants in both community-based cohorts (up to 81% in Malmö) and HFpEF cohorts (up to 75% in MEDIA) in the intermediate-likelihood category, requiring further diagnostic evaluation. Their diagnostic discrimination ranged from moderate to good. The universal definition of HF, SGLT2i trial criteria and NT-proBNP age-adjusted thresholds showed diagnostic performance comparable to HFA-PEFF Scores in the HFpEF cohorts and correctly excluded almost all individuals in the community cohorts. The universal definition of HF demonstrated a diagnostic discrimination higher than H2FPEF and comparable to HFA-PEFF, with the most balanced performance in terms of sensitivity and specificity.ConclusionsUsing scores, a substantial proportion of HFpEF individuals fall into the intermediate likelihood category, highlighting diagnostic uncertainty. Simpler tools, such as the universal definition of HF, demonstrate comparable or even superior diagnostic and rule-out performances for HFpEF, emphasising the need for more practical and reliable approaches to HFpEF diagnosis.

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

Background Cachexia worsens long‐term prognosis of patients with heart failure (HF). Effective treatment of cachexia is missing. We seek to characterize mechanisms of cachexia in adipose tissue, which could serve as novel targets for the treatment. Methods The study was conducted in advanced HF patients (n = 52; 83% male patients) undergoing heart transplantation. Patients with ≥7.5% non‐intentional body weight (BW) loss during the last 6 months were rated cachectic. Clinical characteristics and circulating markers were compared between cachectic (n = 17) and the remaining, BW‐stable patients. In epicardial adipose tissue (EAT), expression of selected genes was evaluated, and a combined metabolomic/lipidomic analysis was performed to assess (i) the role of adipose tissue metabolism in the development of cachexia and (ii) potential impact of cachexia‐associated changes on EAT‐myocardium environment. Results Cachectic vs. BW‐stable patients had higher plasma levels of natriuretic peptide B (BNP; 2007 ± 1229 vs. 1411 ± 1272 pg/mL; P = 0.010) and lower EAT thickness (2.1 ± 0.8 vs. 2.9 ± 1.4 mm; P = 0.010), and they were treated with ~2.5‐fold lower dose of both β‐blockers and angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers (ACE/ARB‐inhibitors). The overall pattern of EAT gene expression suggested simultaneous activation of lipolysis and lipogenesis in cachexia. Lower ratio between expression levels of natriuretic peptide receptors C and A was observed in cachectic vs. BW‐stable patients (0.47 vs. 1.30), supporting activation of EAT lipolysis by natriuretic peptides. Fundamental differences in metabolome/lipidome between BW‐stable and cachectic patients were found. Mitochondrial phospholipid cardiolipin (CL), specifically the least abundant CL 70:6 species (containing C16:1, C18:1, and C18:2 acyls), was the most discriminating analyte (partial least squares discriminant analysis; variable importance in projection score = 4). Its EAT levels were higher in cachectic as compared with BW‐stable patients and correlated with the degree of BW loss during the last 6 months (r = −0.94; P = 0.036). Conclusions Our results suggest that (i) BNP signalling contributes to changes in EAT metabolism in cardiac cachexia and (ii) maintenance of stable BW and ‘healthy’ EAT‐myocardium microenvironment depends on the ability to tolerate higher doses of both ACE/ARB inhibitors and β‐adrenergic blockers. In line with preclinical studies, we show for the first time in humans the association of cachexia with increased adipose tissue levels of CL. Specifically, CL 70:6 could precipitate wasting of adipose tissue, and thus, it could represent a therapeutic target to ameliorate cachexia.

Background Coronary artery disease (CAD) and diabetes mellitus (DM) can induce changes in myocardial structure and function, thereby increasing the risk of heart failure (HF). We aimed to identify the alterations in echocardiographic variables and circulating biomarkers associated with DM, CAD, or both and to assess the effect of spironolactone on them. Methods The “Heart OMics in AGEing” (HOMAGE) trial evaluated the effect of spironolactone on circulating markers of fibrosis over 9 months of follow-up in people at risk for HF. From the initial population ( N  = 527) of the HOMAGE trial, a total of 495 participants (mean age 74 years, 25% women) were categorized according to clinical phenotype (DM-/CAD + vs. DM+/CAD- vs. DM+/CAD+), while the DM-/CAD- group was excluded due to the low sample size ( N  = 32). Multivariable linear regression analysis was used to assess the relations between variables and DM/CAD status. Results At baseline, participants with DM, whether or not they had CAD, showed lower markers of type I collagen synthesis (procollagen type I C-terminal propeptide; β [95% CI]: DM+/CAD-: -6.973 [-13.778; -0.167]; DM+/CAD+: -9.039 [-15.174; -2.903]), reduced left ventricular volumes ( β [95% CI]: end-diastolic, DM+/CAD-: -6.323 [-9.696; -2.951]; DM+/CAD+: -2.503 [-5.531; 0.526]; end-systolic, DM+/CAD-: -2.905 [-4.817; -0.992]; DM+/CAD+: -1.400 [-3.120; 0.320]) and higher levels of galectin-3 (Exponential β [95% CI]: DM+/CAD-: 1.127 [1.050; 1.209]; DM+/CAD+: 1.118 [1.048; 1.192]), and growth differentiation factor-15 (Exponential β [95% CI]: DM+/CAD-: 1.542 [1.360; 1.747]; DM+/CAD+: 1.535 [1.370; 1.720]), along with an elevated E/e’ ratio ( β [95% CI]: DM+/CAD-: 1.355 [0.462; 2.248]; DM+/CAD+: 0.879 [0.067; 1.690]), compared with DM-/CAD + individuals (all p  < 0.05). At follow-up, the effect of spironolactone on echocardiographic variables and circulating biomarkers was not significantly different across DM/CAD phenotypes (all p-interaction > 0.05), except for a more pronounced reduction in GDF-15 in the DM+/CAD + group at the 1-month visit (p-interaction = 0.03). Conclusions Among HOMAGE trial participants, diabetes was a powerful driver of biomarker and echocardiographic alterations irrespectively of CAD. These alterations were mainly related to the domains of inflammation and diastolic function. Graphic abstract Summary of the study design and key findings. Abbreviations: CAD, coronary artery disease; DM, diabetes mellitus; LV, left ventricular; M0, baseline; M1, 1-month follow-up; M9, 9-month follow-up; PICP, procollagen type I C-terminal propeptide.

Abstract Background The use of intravenous (IV) diuretics in an outpatient setting may represent an alternative to conventional hospitalization. Our objective was to identify factors associated with diuretic response during ambulatory IV diuretic sessions in a population of advanced heart failure with no therapeutic project and a frequent flyer profile. Method All patients with 4-h IV diuretic sessions were analysed. An initial bolus followed a tailored protocol for continuous infusion based on the patient's baseline diuretic dose. Variables associated with diuresis and natriuresis following furosemide infusion were evaluated using mixed linear models. Results Seventy-six patients (mean age 75.4 years; LVEF 42.7%; eGFR 40.7 mL/min/1.73 m2) totalling 175 IV diuretic sessions were included. Mean diuresis was 1.0 L, natriuresis 92.6 mmol/L, and weight loss 610 grams. Baseline use of ACE inhibitors (+302 mL, P = 0.0005), eGFR (+160 mL per 10 mL/min/1.73 m2 increase, P < 0.0001), and addition of thiazide during the diuretic session (+238 mL, P = 0.0001) were associated with higher diuresis. Prior percutaneous mitral valve repair or chronic thiazide treatment was associated with lower diuresis. Baseline use of ACE inhibitors (+10.83 mmol/L, P = 0.018) was associated with higher natriuresis. Worsening renal function (>3 mg/L increase from baseline) and dyskalaemia 48 h after these sessions were uncommon (respectively 11% and 15%). Conclusions Ambulatory 4-h IV loop diuretic sessions induced a diuresis of approximately 1000 mL with a substantial sodium content, without causing significant complications. Addition of thiazide during the session increased diuresis and/or natriuresis, and could potentially be implemented to maximize the efficacy of ambulatory IV diuretic therapy.

Patient-reported outcomes (PROs) have been previously considered “soft” end-points because of the lack of association of the reported outcome to measurable biological parameters. The present study aimed to assess whether electrocardiographic measures are associated to PROs changes. We evaluated the association between heart rate ( HR), QRS and QT/QTc durations and PROs, classified as “good” or “bad” according to the patients’ overall feeling of health, in patients from the Chiron project. Twenty-four chronic heart failure (HF) patients were enrolled in the study (71% male, mean age 62.9 ± 9.4 years, 42% ischemic etiology, 15 NYHA class II and 9 class III) providing 1086 days of usable physiological recordings (4 hours/day). The mean HR was significantly higher in the “bad” than in the “good” PROs class (74.0 ± 6.4 bpm vs 68.0 ± 7.2 bpm; p < 0.001). Conversely, the ratio between movement and rest activities showed significantly higher values in “good” compared to “bad” PROs. We also found significantly longer QTc and QRS durations in patients with “bad” PROs compared to patients with “good” PROs. That in patients with mild to moderate HF, higher HR, wider QRS and longer QTc, as well as a reduced HR ratio between movement and rest, were associated with “bad” PROs is clinically noteworthy because the association of worse PROs with measurable variations of biological parameters may help physicians in evaluating PROs reliability itself and in their clinical decisions. Whether a timely intervention on these biological parameters may prevent adverse outcomes is important and deserves to be investigated in further studies.

Takotsubo cardiomyopathy (TCM) is characterized by transient ventricular dysfunction, classically in its apical and mid segments, in the absence of corory lesions, and is often observed after intense stressful events and occasiolly associated to an acute medical illness. We describe a case of TCM associated with corory artery disease and triggered by a percutaneous corory angioplasty. This case highlights the concept that a medical procedure can lead, in certain conditions, to TCM and provides new interesting insights on the pathophysiology of corory syndromes.

Hypertrophic cardiomyopathy (HCM) follows highly variable paradigms and disease-specific patterns of progression towards heart failure, arrhythmias and sudden cardiac death. Therefore, a generalized standard approach, shared with other cardiomyopathies, can be misleading in this setting. A multimodality imaging approach facilitates differential diagnosis of phenocopies and improves clinical and therapeutic management of the disease. However, only a profound knowledge of the progression patterns, including clinical features and imaging data, enables an appropriate use of all these resources in clinical practice. Combinations of various imaging tools and novel techniques of artificial intelligence have a potentially relevant role in diagnosis, clinical management and definition of prognosis. Nonetheless, several barriers persist such as unclear appropriate timing of imaging or universal standardization of measures and normal reference limits. This review provides an overview of the current knowledge on multimodality imaging and potentialities of novel tools, including artificial intelligence, in the management of patients with sarcomeric HCM, highlighting the importance of specific “red alerts” to understand the phenotype–genotype linkage.