Long-term outcomes of phenoclusters in preclinical heart failure with preserved and mildly reduced ejection fraction.

AIMS: The identification of subjects at higher risk for incident heart failure (HF) with preserved ejection fraction (EF) suitable for more intensive preventive programmes remains challenging. We applied phenomapping to the DAVID-Berg population, comprising subjects with preclinical HF, aiming to refine HF risk stratification. METHODS: The DAVID-Berg study prospectively enrolled 596 asymptomatic outpatients with EF > 40% with hypertension, diabetes mellitus or known cardiovascular disease. In this cohort, we performed an unsupervised cluster analysis on 591 patients, including clinical, laboratory, electrocardiographic and echocardiographic parameters. We tested the association between each cluster and a composite outcome of HF/death. RESULTS: The median age was 70 years, 55.5% were males and the median EF was 61.0%. Phenomapping provided three different clusters. Subjects in Cluster 3 were the oldest and had the highest prevalence of atrial fibrillation, the lowest estimated glomerular filtration rate (eGFR), the highest N-terminal pro-brain natriuretic peptide (NT-proBNP) and the largest left atrium. During a median follow-up of 5.7 years, 13.4% of subjects experienced HF/death events (N = 79). Compared with Clusters 1 and 2, Cluster 3 had the worst prognosis (log-rank test: Cluster 3 vs. 1 P < 0.001; Cluster 3 vs. 2 P = 0.008). Cluster 3 was associated with a risk of HF/death 2.5 times higher than Cluster 1 [adjusted hazard ratio (HR) = 2.46, 95% confidence interval (CI) 1.24-4.90]. CONCLUSIONS: Based on phenomapping, older patients with lower kidney function and worse diastolic function might represent a subset of preclinical HF with EF > 40% who deserve more efforts to prevent clinical HF.

Safety and Efficacy of Dapagliflozin in Patients with Heart Failure with Reduced Ejection Fraction: Multicentre Retrospective Study on Echocardiographic Parameters and Biomarkers of Heart Congestion.

Objectives: Dapagliflozin has shown efficacy in clinical trials in patients with heart failure and reduced ejection fraction (HFrEF). However, real-world data on its use and outcomes in routine clinical practice are limited. We aimed to evaluate the utilisation and safety profile of dapagliflozin in a real-world population of HFrEF patients within the Marche region. Methods: Nine cardiology departments within the Marche region retrospectively included HFrEF patients who were initiated on dapagliflozin therapy in an outpatient setting. Data on medical history, comorbidities, echocardiographic parameters, and laboratory tests were collected at baseline and after 6 months. Telephone follow-up interviews were conducted at 1 and 3 months to assess adverse events. We defined the composite endpoint score as meeting at least 50% of four objective measures of improvement among: weight loss, NYHA decrease, ≥50% Natriuretic peptides (NP) decrease, and guideline/directed medical therapy (GDMT) up titration. Results: We included 95 HFrEF patients aged 66 ± 12 years, 82% were men, 48% had ischemic heart disease, and 20% had diabetes. At six months, glomerular filtration rate declined (p = 0.03) and natriuretic peptides levels decreased, on average, by 23% (p < 0.001). Echocardiographic measurements revealed a decrease in pulmonary artery pressure (p < 0.001) and E/e' (p < 0.001). In terms of drug therapy, furosemide dosage decreased (p = 0.001), and the percentage of the target dose achieved for angiotensin receptor-neprilysin inhibitors increased (p = 0.003). By multivariable Cox regression, after adjustment for age, sex, the presence of diabetes/prediabetes, and HF duration, higher baseline Hb concentrations (HR 1.347, 95% CI 1.038-1.746, p = 0.025), and eGFR levels (HR 1.016, 95% CI 1.000-1.033, p = 0.46). Conclusions: In a real-life HFrEF population, dapagliflozin therapy is safe and well-tolerated, improves echocardiographic parameters and biomarkers of congestion, and can also facilitate the titration of drugs with a prognostic impact.

[The IN-HF Registry: the history and the scientific production for the Italian cardiology community]. / Il programma IN-HF: la storia e la produzione scientifica a favore della comunità cardiologica italiana.

The Italian Network on Congestive Heart Failure (IN-CHF) project, later known as IN-HF Online, was launched in 1995 to provide the Italian cardiology community with a digital tool, standardized across the country, for managing outpatients with heart failure (HF), that enabled the creation of a database for clinical, educational and scientific purposes. During its almost three decades of activity, this observational research program has achieved highly positive scientific results. Indeed, IN-HF fostered professional relationships among individuals working in different centers, established a cultural network for the care of HF patients, periodically updated on the scientific advances, and allowed the assessment of several clinical, epidemiological, and prognostic features. These findings have been published in numerous national and international journals, as summarized in the present overview.

[Optimizing the care management pathway of patients with ischemia and non-obstructive coronary arteries]. / Ottimizzazione del percorso clinico-gestionale del paziente con ischemia in assenza di malattia coronarica ostruttiva.

Ischemia with non-obstructive coronary arteries (INOCA) is defined by the coexistence of anginal symptoms and demonstrable ischemia, with no evidence of obstructive coronary arteries. The underlying mechanism of INOCA is coronary microvascular dysfunction with or without associated vasospasm. INOCA patients have recurrent symptoms, functional limitations, repeated access to the emergency department, impaired quality of life and a higher incidence of cardiovascular events than the general population. Although well described in chronic coronary syndrome guidelines, INOCA remains underdiagnosed in clinical practice because of insufficient awareness, lack of accurate diagnostic tools, and poorly standardized and consistent definitions to diagnose, both invasively and non-invasively, coronary microvascular dysfunction.To disseminate current scientific evidence on INOCA as a distinct clinical entity, during 2022 we conducted at 30 cardiology units all over the country a clinical practice improvement initiative, with the aim of developing uniform and shared management pathways for INOCA patients across different operational settings. The present document highlights the outcomes of this multidisciplinary initiative.

Clinical characteristics, treatment, trajectories and outcome of patients with dilated cardiomyopathy in a national heart failure registry.

BACKGROUND: Available data on the clinical characteristics and prognosis of patients with heart failure (HF) due to dilated cardiomyopathy (DCM) derive mainly from tertiary care centres for cardiomyopathies or from drug trial sub-studies, which may entail a referral bias. METHODS: From 2008 to 2021, we enrolled in a nationwide HF Registry 1886 DCM patients and 3899 with ischemic heart disease (IHD). RESULTS: Patients with DCM were younger, more often female, had more commonly recent onset HF, left bundle branch block, and showed higher LV end-diastolic volume and lower LVEF than IHD. With respect to IHD, DCM patients received more often mineralocorticoid receptor antagonists, renin angiotensin system inhibitors and betablockers, the latter more commonly at doses ≥50% of target, and triple guideline-directed medical therapy (GDMT) (adjusted OR 1.411, 95% CI 1.247-1.595, p < .0001). During one-year follow-up, 819 patients (14.2%) died or were hospitalized for HF [187 (9.9%) DCM, 632 (16.2%) IHD]; DCM was associated with lower risk of the combined end-point (adjusted HR 0.745, 95% CI 0.625- 0.888, p = .0011). Among the 1954 patients with 1-year echocardiograms available, 1483 had LVEF≤40% at baseline; of these,166 (30.6%) DCM and 165 (17.5%) IHD improved their LVEF to >40% (p < .0001). DCM aetiology was associated with higher likelihood of LVEF improvement (adjusted OR 1.722, 95% CI 1.328 -2.233, p < .0001). CONCLUSIONS: DCM patients have a different clinical profile, greater uptake of GDMT and better outcomes than IHD subjects. A comprehensive management approach is needed to further address the risk of unfavorable outcomes in DCM.

[Pulmonary hypertension associated with left heart diseases: pathophysiology, diagnosis, treatment]. / Ipertensione polmonare associata ad insufficienza cardiaca: fisiopatologia, diagnosi, terapia.

Pulmonary hypertension (PH) is a common complication of diseases affecting the left heart, mostly found in patients suffering from heart failure. Left atrial hypertension is the initial driver of post-capillary PH. However, several mechanisms may lead in a subset of patients to structural changes in the pulmonary vessels with development of a pre-capillary component. The right ventricle may be frequently affected, leading to right ventricular failure and a worse outcome. The differential diagnosis of PH associated with left heart disease vs pulmonary arterial hypertension (PAH) is challenging in patients with cardiovascular comorbidities, risk factors for PAH and/or a preserved left ventricular ejection fraction. Multidimensional clinical phenotyping is needed to identify patients in whom hemodynamic confirmation is deemed necessary, that may be completed by provocative testing in the cath lab. In contrast with PAH, management of PH associated with left heart disease should focus on the treatment of the underlying condition. There is currently no approved therapy for PH associated with left heart disease: some PAH-specific treatments have led to an increase in adverse events in these patients.

[Ten questions on cardiac magnetic resonance in patients with heart failure: from etiological diagnosis to prognostic stratification]. / Dieci quesiti in tema di risonanza magnetica cardiaca nel paziente con scompenso cardiaco: dalla diagnosi eziologica alla stratificazione prognostica.

Cardiac magnetic resonance (CMR) imaging has progressively become part of the imaging methods recommended in patients with heart failure. CMR represents the gold standard for assessing volumes, function, biventricular kinetics and providing tissue characterization through scans with and without contrast medium. In patients with heart failure with reduced ejection fraction (HFrEF) and ischemic dilated cardiomyopathy, CMR allows to search for viability, accurately estimate volumes and ejection fraction. It can assess scar extent for predicting response to cardiac resynchronization therapy and for establishing an indication for implanting a defibrillator in borderline cases. In patients with HFrEF and non-ischemic dilated cardiomyopathy, CMR helps to identify specific etiological subgroups and to estimate the arrhythmic risk beyond ejection fraction. In patients with heart failure with preserved ejection fraction, CMR offers the possibility of diagnosing specific phenotypes, including sarcomeric hypertrophic cardiomyopathy, amyloidosis or Fabry disease, and adds prognostic information. Both clinical and scientific interest in this imaging method is constantly expanding; the clinicians dealing with heart failure cannot fail to know the technique, the indications and all the potential that CMR can offer.

[Heart failure with improved ejection fraction: practical guidance for the clinician]. / Lo scompenso cardiaco con frazione di eiezione migliorata: indicazioni gestionali per il clinico.

Heart failure with improved ejection fraction (HFimpEF) represents a nosological entity that has recently been recognized and has little evidence from the literature. Available data indicate an increasing incidence of this patient group, consistent with the progressive improvement and implementation of medical therapy of heart failure with reduced ejection fraction (HFrEF). Furthermore, it is important to underline that the therapy itself should not be suspended after ejection fraction recovery, to avoid the recurrence of worse systolic dysfunction and patient outcomes. Only recently a randomized clinical study has been published, which enrolled also this patient subgroup, the DELIVER trial. Other data will soon become available, given the interest of the scientific community for this subgroup of patients, whose best management remains controversial. Since many studies suggest that the probability of myocardial recovery in HFrEF patients might be as high as 40%, depending on the case series taken into account, whereas the time to recovery might even be 12 months, the appropriate timing of device implantation, such as the defibrillator, in this setting deserves careful consideration.

Combined Neuro-Humoral Modulation and Outcomes in Patients with Chronic Heart Failure and Mildly Reduced or Preserved Ejection Fraction.

Pharmacotherapy of chronic heart failure with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF) remains challenging. We aimed to assess whether combined neuro-humoral modulation (NHM) (renin−angiotensin system inhibitors, betablockers, mineralocorticoid receptor antagonists) was differentially associated with outcome according to phenotype and age groups. Between 1999 and 2018 we recruited in a nationwide cardiology registry 4707 patients (HFmrEF n = 2298, HFpEF n = 2409) from three age groups: <65, 65−79 and 80+ years old. We analyzed clinical characteristics and 1 year all-cause mortality/cardiovascular hospitalization according to none/single, any double, or triple NHM. Prescription rates of no/single and triple NHM were 25.1% and 26.7% for HFmrEF; 36.5% and 17.9% for HFpEF patients, respectively. Older age was associated with higher prescription of no/single NHM in HFmrEF (ptrend = 0.001); the reverse was observed among HFpEF (ptrend = 0.005). Triple NHM increased over time in both phenotypes (all p for trend < 0.0001). Compared to no/single NHM, triple, but not double, NHM was associated with better outcomes in both HFmrEF (HR 0.700, 95%CI 0.505−0.969, p = 0.032) and HFpEF (HR 0.700, 95%CI 0.499−0.983, p = 0.039), with no interaction between NHM treatment and age groups (p = 0.58, p = 0.80, respectively). In a cardiology setting, among HF outpatients with EF > 40%, triple NHM treatment increased over time and was associated with better patient outcomes.

Temporal trends in characteristics, treatment, and outcomes of heart failure in octogenarians over two decades.

INTRODUCTION AND OBJECTIVES: Octogenarians represent the most rapidly expanding population segment in Europe. The prevalence of heart failure (HF) in this group exceeds 10%. We assessed changes in clinical characteristics, therapy, and 1-year outcomes over 2 decades in chronic HF outpatients aged ≥ 80 years enrolled in a nationwide cardiology registry. METHODS: We included 2520 octogenarians with baseline echocardiographic ejection fraction measurements and available 1-year follow-up, who were recruited at 138 HF outpatient clinics (21% of national hospitals with cardiology units), across 3 enrolment periods (1999-2005, 2006-2011, 2012-2018). RESULTS: At recruitment, over the 3 study periods, there was an increase in age, body mass index, ejection fraction, the prevalence of obesity, diabetes, dyslipidemia, pre-existing hypertension, and atrial fibrillation history. The proportion of patients with preserved ejection fraction rose from 19.4% to 32.7% (P for trend <.0001). Markers of advanced disease became less prevalent. Prescription of beta-blockers and mineralocorticoid receptor antagonists increased over time. During the 1-year follow-up, 308 patients died (12.2%) and 360 (14.3%) were admitted for cardiovascular causes; overall, 591 (23.5%) met the combined primary endpoint of all-cause mortality or cardiovascular hospitalization. On adjusted multivariable analysis, enrolment in 2006 to 2011 (HR, 0.70; 95%CI, 0.55-0.90; P=.004) and 2012 to 2018 (HR, 0.61; 95%CI, 0.47-0.79; P=.0002) carried a lower risk of the primary outcome than recruitment in 1999 to 2005. CONCLUSIONS: Among octogenarians, over 2 decades, risk factor prevalence increased, management strategies improved, and survival remained stable, but the proportion hospitalized for cardiovascular causes declined. Despite increasing clinical complexity, in cardiology settings the burden of hospitalizations in the oldest old with chronic HF is declining.

[ANMCO Position paper: Care pathway for advanced heart failure patients candidate for heart transplantation/ventricular assist device]. / Position paper ANMCO: Percorso assistenziale del paziente con insufficienza cardiaca avanzata candidabile a trapianto/assistenza ventricolare meccanica.

Heart failure is a complex clinical syndrome with a severe prognosis, despite therapeutic progress. The management of the advanced stages of the syndrome is particularly complex in patients who are referred to palliative care as well as in those who are candidates for cardiac replacement therapy. For the latter group, a prompt recognition of the transition to the advanced stage as well as an early referral to the centers for cardiac replacement therapy are essential elements to ensure that patients follow the most appropriate diagnostic-therapeutic pathway. The aim of this document is to focus on the main diagnostic and therapeutic aspects related to the advanced stages of heart failure and, in particular, on the management of patients who are candidates for cardiac replacement therapy.

Epidemiology of cardiomyopathies: essential context knowledge for a tailored clinical work-up.

Cardiomyopathies (CMPs) are primary disorders of myocardial structure and function in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease. Knowledge of the incidence and prevalence of CMPs may help clinicians to compare their observations in clinical practice with expected cases per person-year and to avoid under-reporting in clinical context. Currently, available estimates of prevalence and incidence of CMPs are based on clinical data, collected with a wide variability in population-source, and before the genetic testing evolved as a standard diagnostic tool. This review focuses on the epidemiology of CMPs in subjects aged between 18 and 55 years. A structured up-to-date diagnostic flow-chart for CMPs diagnosis and assessment is proposed to avoid misdiagnosis of CMPs in the young population and in subjects with unexplained cardiac disorders.

Age-related changes in clinical characteristics and outcomes of chronic heart failure outpatients in a cardiology setting. A report from the Italian Network on Heart Failure.

AIMS: Ageing and comorbidities are increasing frailty/complexity of heart failure (HF) patients globally. We assessed evolving trends over two decades according to patients' age and time of recruitment in a nationwide cardiology setting in Italy. METHODS AND RESULTS: Chronic HF outpatients recruited between 1999 and 2018 (N = 14,823) were divided into 3 cohorts: 1999-2005 (N = 5404); 2006-2011 (N = 3971); 2012-2018 (N = 5448). We analyzed temporal changes in clinical characteristics, therapies, and outcome (1-year all-cause mortality/cardiovascular hospitalization), overall and by age group: <65 (n = 5465); 65-79 (n = 6838); ≥80 (n = 2520) years old. Across enrolment epochs, comorbidities (atrial fibrillation, hypertension, obesity) increased by both epoch/age groups (p < 0.001), whereas the prevalence of ischemic etiology declined among patients ≥65 years (p = 0.05). Accordingly, the preserved LVEF phenotype (HFpEF) increased in all age categories (p < 0.001) over time. Moreover, the use of betablockers, mineralocorticoid-receptor antagonists and loop-diuretics rose by enrolment epoch in all age groups (p < 0.05). In parallel with these epidemiologic/treatment changes, age-adjusted survival free from cardiovascular hospitalization improved over time (p < 0.0001). However, divergent trends in the end-point components were apparent according to age groups: mortality decreased in patients<80 years, although hospitalizations remained stable in the youngest group, while subjects ≥65 years were less likely to be admitted for cardiovascular causes (all p < 0.005). CONCLUSIONS: Over two decades in a cardiology outpatient setting, the prevalence of comorbid HFpEF increased in all age categories. Mortality improved among patients<80 years and cardiovascular hospitalizations decreased in patients≥65 years. These findings point to the value of cardiologist' input in the management of adult chronic HF patients at all ages.

Gender-Specific Behaviour in Obesity Stages I-II: Imbalance of Aminothiol Status and Adipomyokine Profile in Subjects with Different Insulin Resistance Severity.

The hyperproduction of oxidative stress and inflammatory biomarkers, which is paralleled by decreased levels of antioxidant and anti-inflammatory mediators, is part of cellular mechanisms that contribute to the disruption of metabolic homeostasis in obesity. Whether gender-specific alterations and gender-restricted associations in these biomarkers underlie the increased cardiometabolic risk in men compared to women is unclear. We enrolled 31 women and 29 men, aged ≥50 and ≤70 years and with body mass index ≥ 30 and <40 kg/m2. We assessed the concentrations of aminothiols (cysteine, homocysteine, and glutathione), expression of oxidant/antioxidant balance, adipomyokines (leptin, adiponectin, myostatin, and interleukin-6), markers of chronic inflammation, and vitamin D, an index of nutritional state, in plasma and serum samples by using HPLC, ELISA, and chemiluminescent immunoassay methods. We measured insulin resistance (IR) by the homeostasis model assessment (HOMA) index. Despite comparable levels of visceral adiposity, IR, and a similar dietary regimen, men showed, with respect to women, higher oxidant concentrations and lower antioxidant levels, which paralleled IR severity. Myostatin levels correlated with prooxidant aminothiols among men only. Gender-specific alterations in aminothiol status and adipomyokine profile and the gender-restricted association between these biomarkers and metabolic derangement are consistent with an increased cardiometabolic risk in men compared to age-matched women with stage I-II obesity. Strict control of redox and inflammatory status, even addressing gender-specific nutritional targets, may be useful to prevent obesity-related metabolic alterations and comorbidities.

Integrating natriuretic peptides and diastolic dysfunction to predict adverse events in high-risk asymptomatic subjects.

BACKGROUND: Natriuretic peptides and diastolic dysfunction have prognostic value in asymptomatic subjects at risk for heart failure. Their integration might further refine the risk stratification process in this setting. Aim of this paper was to explore the possibility to predict heart failure and death combining diastolic dysfunction and natriuretic peptides in an asymptomatic population at risk for heart failure. METHODS: Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for heart failure. Baseline evaluation included electrocardiogram, echocardiogram, and natriuretic peptides collection. Based on diastolic dysfunction and natriuretic peptides, subjects were classified in four groups: control group (no diastolic dysfunction/normal natriuretic peptides, 57%), no diastolic dysfunction/high natriuretic peptides (9%), diastolic dysfunction/normal natriuretic peptides (24%), and diastolic dysfunction/high natriuretic peptides (11%). We applied Cox multivariable and Classification and Regression Tree analyses. RESULTS: The mean age of the population was 69 ± 7 years, 44% were women, mean left ventricular ejection fraction was 61%, and 35% had diastolic dysfunction. During a median follow-up of 5.7 years, 95 heart failure/death events occurred. Overall, diastolic dysfunction and natriuretic peptides were predictive of adverse events (respectively, hazard ratio 1.91, confidence interval 1.19-3.05, padjusted = 0.007, and hazard ratio 2.25, confidence interval 1.35-3.74, padjusted = 0.002) with Cox analysis. However, considering the four study subgroups, only the group with diastolic dysfunction/high natriuretic peptides had a significantly worse prognosis compared to the control group (hazard ratio 4.48, confidence interval 2.31-8.70, padjusted < 0.001). At Classification and Regression Tree analysis, diastolic dysfunction/high natriuretic peptides was the strongest prognostic factor (risk range 24-58%). CONCLUSIONS: The DAVID-Berg data suggest that we look for the quite common combination of diastolic dysfunction/high natriuretic peptides to correctly identify asymptomatic subjects at greater risk for incident heart failure/death, thus more suitable for preventive interventions.

Correlates of olfactory impairment in middle-aged non-diabetic Caucasian subjects with stage I-II obesity.

PURPOSE: This study evaluates among middle-aged subjects with obesity the prevalence of olfactory impairment (OI) with respect to normative values and its correlation with body composition, cognition, sleep quality, and inflammation. METHODS: In 60 (31 women, 29 men) volunteers with a body mass index ≥ 30 to ≤ 40 kg/m2, aged ≥ 50 to ≤ 70 years, we assessed olfaction by the Sniffin' Stick test. We measured anthropometrics, body composition and metabolic profiles and evaluated cognition by the MiniMental State Examination (MMSE) and sleep disturbances by the Insomnia Severity Index (ISI). Patients were classified into two groups according to a total olfactory score (odor Threshold, Discrimination, Identification, TDI) below or above the 25th percentile from age and gender-adjusted normative data. RESULTS: Overall, 25 subjects (42%) had OI (TDI < 25th percentile). The largest differences between subjects with and without OI were observed in discrimination and identification scores, with a large overlap in olfactory threshold. Subjects with an abnormal TDI showed significantly higher fat mass index, ISI scores and urinary neopterin and lower MMSE scores than those without OI. By multivariable logistic regression, MMSE, ISI score and urinary neopterin were significantly associated to OI. CONCLUSIONS: Among middle-aged subjects with stage I and II obesity, OI is highly prevalent and is independently associated with poor self-reported sleep quality, lower cognition scores and higher levels of the inflammatory marker neopterin.

Heart Failure With Mid-range or Recovered Ejection Fraction: Differential Determinants of Transition.

The recent definition of an intermediate clinical phenotype of heart failure (HF) based on an ejection fraction (EF) of between 40% and 49%, namely HF with mid-range EF (HFmrEF), has fuelled investigations into the clinical profile and prognosis of this patient group. HFmrEF shares common clinical features with other HF phenotypes, such as a high prevalence of ischaemic aetiology, as in HF with reduced EF (HFrEF), or hypertension and diabetes, as in HF with preserved EF (HFpEF), and benefits from the cornerstone drugs indicated for HFrEF. Among the HF phenotypes, HFmrEF is characterised by the highest rate of transition to either recovery or worsening of the severe systolic dysfunction profile that is the target of disease-modifying therapies, with opposite prognostic implications. This article focuses on the epidemiology, clinical characteristics and therapeutic approaches for HFmrEF, and discusses the major determinants of transition to HFpEF or HFrEF.

Inhibidores del sistema renina-angiotensina y pronóstico durante tratamiento con hidroxicloroquina en pacientes hospitalizados por neumonía por COVID-19 / Renin-angiotensin system blockers and outcomes during hydroxychloroquine treatment in patients hospitalized for COVID-19 pneumonia

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