2025 SIC意见书：心力衰竭非心血管合并症（更新版）

Non cardiovascular comorbidities in Heart Failure. An updated position paper from the Heart Failure Working Group of the Italian Society of Cardiology (SIC)

Michele Correale $^{a}$,1,*, $^{D}$,Andrea Salzano $^{b}$,c,d,1,Lucia Tricarico $^{a}$,D, Antonio Cittadini $^{b}$,c, Giulia Crisci $^{c}$, Giuseppe Dattilo $^{f}$, Riccardo Maria Inciardi $^{g}$, Emiliano Fiori $^{h}$,Stefania Paolillo $^{d}$, Gaetano Ruocco $^{1}$,Angela Sciacqua $^{m}$,Paolo Severino $^{n}$,Valentina Mercurio $^{b,0}$, Piergiuseppe Agostoni $^{p}$, Francesco Barillà $^{q}$, Frank Lloyd Dini $^{r}$,Pasquale Perrone Filardi $^{i}$, Savina Nodari $^{g,2}$, $^{D}$, Alberto Palazzuoli $^{s,2}$, on behalf of the Italian Society of Cardiology (ISC) Working Group on Heart Failure $^{3}$

a Cardiothoracic Department, 'Policlinico Riuniti' University Hospital, 71100 Foggia, Italy

$^{b}$ Department of Translational Medical Sciences, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples, Italy

c'Interdepartmental Center for Research in Gender Medicine-GENESIS, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples, Italy

c Cardiac Unit, AORN A Cardarelli, 80131, Naples, Italy

e Department of Cardiology, University of Milan, School of Medicine, San Paolo Hospital, Milano, Italy

${}^{f}$ Department of Biomedical, Dental Sciences, and Morphofunctional Imaging, University of Messina, Messina, Italy

§ Section of Cardiology, Department of Medical and Surgical Specialities, Radiological Sciences, and Public Health, University of Brescia, Italy

hDepartment of Clinical and Molecular Medicine, University "La Sapienza, Rome, Italy

$^{i}$ Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy

${}^{1}$ Cardiology Unit, "I. Veris Deli Ponti" Hospital, ASL Lecce, Scorrano, Italy

m Geriatrics Division, "Renato Dulbecco" University Hospital of Catanzaro 88100 Italy; Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy

$^{6}$ Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Polliclinico 155, 00161 Rome, Italy

$^{0}$ Interdepartmental Center for Clinical and Translational Research (CIRCET), Federico II University, Naples, Italy

$^{P}$ Centro Cardiologico Monzino, IRCC Milan, Italy. Department of Clinical Sciences and Community Health, Cardiovascular Section, University of Milan, Milan, Italy

$^{4}$ Cardiology Unit, University of Tor Vergata Rome, Rome, Italy

${}^{5}$ Department of Cardiology, San Luca Hospital, Istituto Auxologico Italiano, IRCCS, Milan, Italy

$^{5}$ Cardio Thoracic and Vascular Department, 'S. Maria alle Scotte Hospital', University of Siena, 53100 Siena, Italy

ARTICLE INFO

Keywords:

Heart failure

COPD

Cardio-oncology

Chronic kidney disease

Sleep apnea

Diabetes

Obesity

Hormones

ABSTRACT

Heart Failure (HF) is frequently associated with various non cardiovascular (CV) comorbidities significantly impacting HF prognosis. Indeed, the simultaneous presence of multiple diseases leads to an increased vulnerability, with frailty occurrence. This status implies poor quality of life and increased adverse events rate in terms of hospitalization and mortality. Therefore, the most recent trials and observational studies indicate non-CV comorbidities as new targets for novel management strategies and drugs; however, there is still the need to better understand the pathophysiology of non-CV comorbidities and the possible interplay between non-CV comorbidities and HF. Additionally, metabolic, and multiple organ diseases reduce the use and the achievement of targeted doses of HF Guideline-directed medical therapy (GDMT), due to potential adverse effects, exposing patients to further clinical events. Finally, non-CV comorbidities burden demonstrated different prevalence and prognostic impact according to HF phenotypes, impacting on the disease progression. Therefore, in order to provide physicians and researchers engaged in the “fight against heart failure” an updated practice

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guide, the Working Group on Heart Failure of the Italian Society of Cardiology (ISC) offers a revised manifesto on the relationship between non-CV comorbidities and HF.

1. Introduction

Heart Failure (HF) affects more than 64 million people worldwide [1]. While the incidence of HF has stabilized, its prevalence is increasing due to the ageing of the population, improvements in the treatment of major causes (e.g., coronary artery disease -CAD) leading to better survival, and the availability of evidence-based therapies prolonging life [1].

The presence of comorbidities, particularly common in the elderly and in the preserved ejection fraction (HFpEF) phenotype, is associated with more severe symptoms and signs. This association has two main repercussions: it can cause confusion in distinguishing symptoms effectively related to HF syndrome, and it impairs the whole clinical status and quality of life[2]. Indeed, conditions such as anemia, diabetes mellitus, renal diseases, chronic lung diseases, sleep apnea, and cognitive neurological disorders negatively affect the prognosis, independently from HF status and evolution[3] Notably, some non-cardiovascular (non-CV) comorbidities (e.g., chronic obstructive pulmonary disease -COPD, diabetes mellitus, anemia, obesity) are more prevalent in HFpEF patients[4]. Conversely, other non-CV, (e.g., cachexia, neoplastic disease, hormonal disturbances) are more common in HF with reduced ejection fraction (HFrEF). Furthermore, a systemic proinflammatory state induced by comorbidities may be the main cause of myocardial structural and functional alterations in HFpEF[5]. This underlines the different roles and impacts of comorbidities in HF and highlights the importance of targeting comorbidities in both HFpEF and HFrEF.

Early recognition and management of associated diseases may be as important as HF treatment itself, impacting on HF progression and prognosis. However, there is a limited understanding of the intricate relationships between HF and associated comorbidities. Recently, it has been emphasized the importance of focusing on some specific non-CV comorbidities for individualized risk stratification and optimal management in patients with HFpEF[6].

Together with the management of CV comorbidities, the

management of non-CV comorbidities represents a novel field of interest requiring a specific and dedicated focus. Since the publication, in the 2019, of the Italian Society of Cardiology (ISC) Working Group on HF manifesto about comorbidities in HF$^{2}$, several are the novel evidence from literature emerged. Therefore, the aim of the present updated position paper is to review, update and synthesize the evidence about the management of non-CV comorbidities in HF (Fig. 1 and Table 1), emphasizing the need for a multidisciplinary and tailored approach.

2. Methods

Three 'in-person' and three 'online' meetings were conducted by the member of the HF working group of the Italian Society of Cardiology. These meeting were specifically focused on discussing and selecting the non-CV comorbidities, reviewing the results of the literature search, and forming a panel opinion on the main topics. Specifically, a focused literature search was performed on PubMed until January 2025 to identify relevant original research and review articles. The search used the following main keywords, alone or in logic combination: chronic obstructive pulmonary disease; cancer; chronic kidney disease; obstructive and central sleep apnea; diabetes; hypothyroidism and hyperthyroidism; anabolic hormones; sarcopenia; cachexia; iron deficiency; depression; cognitive impairment. Only articles in English were selected for the review, which prioritize the most consistent, recent, and relevant trials and original research, preferentially involving human subjects. Titles. Tiles and abstracts from the search were reviewed, full text articles were obtained for relevant manuscripts, and reference lists were reviewed to identify additional manuscripts appropriate for the expert opinion panel.

A reviewer committee (MC, AS, AP) collected and revised all the collected information and completed the final manuscript.

 Fig. 1. Non-Cardiovascular (Non-CV) comorbidities in HF patients. HF is at the center of all comorbidities. Non-CV comorbidities contribute to HF development, progression and prognosis. The severity of HF may affect some non-cv comorbidities in HF patients (red arrows).

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Table 1

. Non-Cardiovascular Comorbidities in HF.

|System|Comorbidity|Impact on HF|Expert panel opinion| |---|---|---|---| |Respiratory|Chronic Obstructive Pulmonary Disease (COPD) Sleep- Disordered Breathing (SDB)|Increases HF-related hospitalizations, worsens dyspnea and functional capacity Includes obstructive (OSA) and central sleep apnea (CSA), worsening HF symptoms and|● Prefer selective β-blockers (vs nonselective), ● Concerns on long-acting β2-agonists ● CPAP for OSA ● ASV caution in CSA| |Endocrine/ Metabolic|Diabetes Mellitus (DM)|Increasing mortality Bidirectional link with HF, increases mortality and hospitalizations|● SGLT2 inhibitors as first-line treatment ● GLP-1 RA in HFEFEF ● Investigate for HD ● Hormone replacement ● Investigation (GH, therapy, testosterone) under investigation| |Neuropsychiatric|Depression & Cognitive Impairment|Includes GH, testosterone, thyroid, and insulin resistance, contributing to HF severity|● Investigate for HD ● Hormone replacement ● Investigation (GH, therapy, testosterone) under investigation| |Renal|Chronic Kidney Disease (CKD)|Common in HF, tests on 31-12|● In addition, some of the mechanisms with an established role in the pathophysiology of HF (i.e., the hyperactivation of both renin-angiotensin-aldosterone system-RAAS, and sympathetic nervous system), may also play a role in the development and expansion of cancer cells[23-25]. Moreover, there is a growing body of evidence demonstrating that a chronic low-grade inflammatory state is common to both HF and cancer, and it may have a role as possible driver in the bidirectional relationship[26-32]. Such intricate correlation between cancer and HF has led to the development of the new concept of 'reverse Cardio-Oncology', which refers to the cancer development in patients with cardiovascular disease[33].| |Oncologic|Cancer|Increased HF risk from cardotoxic cancer treatments; shared risk factors like smoking and obesity|● Close monitoring Cardio-oncology collaboration| |Hematologic/ Nutritional|Anemia and Iron Deficiency|Impairs oxygen transport and cardiac function, worsens HF cardiac function, worsens HF outcomes|● IV iron supplementation safe and effective OS iron supplementation under investigation| ||Cardiac Cachexia|Advanced HF condition, associated with high mortality|● Need for specific treatment ● Early detection needed|

3. Cancer

3.1. Epidemiology and pathophysiology

HF and cancer represent the most common chronic diseases with major health burdens in developed countries, and their incidence and prevalence are expected to increase further as the population ages. Such clinical conditions are strictly interconnected, as HF can be a clinical manifestation of cardiovascular toxicity caused by several antineoplastic drugs. This phenomenon represents the main focus of the new discipline called 'cardio-oncology'[7-10]. Furthermore, aside from the cardiotoxic effect of antineoplastic drugs, increasing epidemiological evidence indicates that HF patients have a higher risk of developing cancer, and vice versa[11-18]. This is partly due to shared risk factors, such as smoking, aging, and metabolic syndrome (including obesity, insulin resistance, and arterial hypertension)[19-22]. In addition, some of the mechanisms with an established role in the pathophysiology of HF (i.e., the hyperactivation of both renin-angiotensin-aldosterone system-RAAS, and sympathetic nervous system), may also play a role in the development and expansion of cancer cells[23-25]. Moreover, there is a growing body of evidence demonstrating that a chronic low-grade inflammatory state is common to both HF and cancer, and it may have a role as possible driver in the bidirectional relationship[26-32]. Such intricate correlation between cancer and HF has led to the development of the new concept of 'reverse Cardio-Oncology', which refers to the cancer development in patients with cardiovascular disease[33].

3.2. Clinical impact

It is unknown whether one condition precedes the other, but the overlap of HF and cancer leads to an extremely challenging clinical condition, where the presence of one can hinder the treatment of the other. Indeed, patients with HF show the highest risk of developing cardiovascular toxicity due to anticancer treatment[7,34,35]. In addition, the need for pharmacological HF therapies optimization may delay the initiation of the anti-neoplastic treatments. Once oncologic treatment has begun, a close follow-up is needed to promptly intercept the development of cardiotoxic effects, as well as the signs and symptoms of worsening HF, to adequately adjust outpatient therapy in order to prevent hospitalization and/or discontinuation of cancer treatment[7,12,36-39]. On the other hand, a cancer diagnosis can complicate HF, especially HFrEF; indeed, the possible development of hypotension, electrolyte imbalance, and acute worsening of renal function (often caused by vomiting and/or diarrhea), may limit the use of HF-specific drugs. Also, the implantation of cardioverter-defibrillator may be held back if life expectancy is estimated to be shorter than one year[40], even though potential benefit patients may have with modern target anti-tumor therapies, that might prolong progression-free survival. Similarly, an active malignancy with a life expectancy of less than 2 years represents an absolute contrain-dication for mechanical circulatory support with a left ventricular assist device (LVAD), neither as destination therapy, nor as bridge-to-transplant indication[41]. Finally, active cancer represents an absolute exclusion criterion from cardiac transplantation[42].

4. Respiratory disorders

Even if HF patients can virtually experience all respiratory disorders, two are the most prevalent: sleep-disordered breathing (SBD), which includes obstructive sleep apnea syndrome (OSAS) and central sleep apnea (CSA), and Chronic obstructive pulmonary disease (COPD).

4.1. Sleep-disordered breathing

In patients with HF, sleep-disordered breathing (SDB), comprising obstructive sleep apnea syndrome (OSAS) and central sleep apnea

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(CSA), is associated with increased morbidity and mortality. In HF patients with SDB caused by OSA, nocturnal hypoxemia can be treated with nocturnal oxygen supplementation, continuous positive airway pressure (CPAP), bi-level positive airway pressure, and adaptive servoventilation (ASV). However, none of these interventions have demonstrated clear beneficial effects on outcomes in HF[43]. CPAP improves blood oxygen saturation and sleep quality in elderly patients with HF complicated with OSAS and reduces NT-pro-BNP level[44]. In addition, CPAP treatment in patients with OSAS, HF, and implantable cardioverter-defibrillators (ICD) showed to have beneficial effects on reducing premature ventricular contractions and electrocardiographic arrhythmia indices[45]. On the other hand, when SDB is determined by CSA, CPAP is contraindicated in HFrEF patients[46] as well as the use of ASV, based on the results of SERVE-HF[46], which was neutral regarding the primary endpoint of a composite of death from any cause or lifesaving CV intervention, but showed an increase in both all-ay cause mortality and CV mortality with ASV. However, despite showing no effect on the primary composite outcome or mortality, the ADVENT-HF trial showed ASV to be able to eliminate SDB safely[47]. Finally, implantable phrenic nerve stimulation may serve as a therapeutic approach for CSA[48]. Overall, the treatment of CSA in HFrEF appears to be a challenge for clinicians and requires further multicenter studies.

4.2. Chronic obstructive pulmonary disease (COPD)

4.2.1. Epidemiology and pathophysiology

One in five patients with HF also is affected by COPD, a combination that worsens prognosis in both chronic and acute settings[49]. On the other hand, although HF is often underdiagnosed, it is the most common cardiovascular condition found in patients with COPD when proactive screening is conducted[50].

The coexistence of COPD and HF synergistically impairs functional capacity, creating a "cardiopulmonary continuum" [51–53]. HF patients typically experience dyspnea during exertion due to basal ventilatory restriction, respiratory muscle fatigue, and increased breathing effort caused by an exaggerated ventilatory response. This response is driven by sympathetic overstimulation of chemoreceptors and metaboreflex activation resulting from respiratory and skeletal muscle exhaustion. Additionally, the alveolar-capillary unit undergoes unfavorable remodeling due to impaired alveolar clearance [54] in both chronic and acute hemodynamic stress [55], leading to a reduction in overall lung diffusion capacity. In this context, COPD—characterized by airway obstruction and hyperinflation—causes abnormal mechanical changes in the diaphragm[56], which in turn affects central hemodynamics and impairs left ventricular (LV) filling, limiting both cardiac output and stroke volume during exercise.

4.2.2. Clinical impact

Due to overlapping symptoms and signs, distinguishing between HF and COPD, and assessing their individual clinical impacts, can be challenging. While pulmonary function testing (PFT) is recommended as a primary diagnostic tool for COPD, its specificity is limited in HF because clinical stability and airway obstruction associated with HF are dynamic [57]. In this regard, cardiopulmonary exercise testing (CPET) parameters, particularly the analysis of the ventilatory efficiency slope intercept (VEint), may be useful in differentiating COPD from HF[58]. Regarding laboratory tests, natriuretic peptide levels—specifically N-terminal pro-BNP—maintain their diagnostic value in acute HF regardless of age or the presence of COPD[59].

Recent studies suggest that HF patients with COPD are approximately 10 % less likely to be prescribed β-blockers, due to outdated concerns about their effects on small airways[60]. However, it is important to emphasize that COPD is not a conirdainction for β-blocker use, with β1-selective agents preferred for their minimal impact on distal airways and lung diffusion[61]. In cases of coexisting HFFrEF, COPD, and right-sided HF, β-blockers have been shown to

prevent cardiac decomposition, pulmonary congestion, and even COPD exacerbations[62]. Conversely, safety concerns remain regarding the use of long-acting β2-agonists as bronchodilators in COPD patients with HF, although clear evidence is lacking and retrospective data from real-life settings suggest only a modest increase in HF-related events [63]. Finally, exercise training deserves special mention in the management of both HF and COPD, as it has been shown to improve aerobic capacity, left ventricular function, and secondary functional outcomes [64].

5. Endocrine and metabolic disorders

Several links exist between endocrine disturbances and HF; indeed, it has been demonstrated that these conditions share several pathophysiological pathways, that the coexistence of endocrine and metabolic disorders negatively impact on HF prognosis, and that targeted endocrine and metabolic treatments are able to improve quality of life, cardiovascular performance, and prognosis of HF patients.

In the following paragraphs, a summary about these in-terconnections is depicted.

5.1. Obesity

Obesity is one of the main emerging health problems of the 21st century, with a prevalence that has more than doubled over the last 40 years[65]. Notably, a bidirectional link exists between obesity and the HFpEF phenotype. Indeed, many studies have linked HFpEF with obesity and, as expected, more than 80 % of patients with HFpEF in the United States are overweight or obese[66]. From a pathophysiological point of view, this connection mainly depends on the inflammation promoted by increased adiposity. In fact, adipose tissue can be considered an endocrine organ capable of secreting various substances, including proinflammatory cytokines[67]. Specifically, Interleukin-6 and Tumor Necrosis Factor-alpha (TNF-α) promote protein catabolism in the skeletal muscle[68], while other mediators, such as myostatin, may also contribute to the pathogenesis[69]. Overall, obese patients with HFpEF show a higher degree of concentric left ventricular remodeling, right ventricular dilatation and dysfunction, and increased epicardial fat thickness[70]. Further supporting this link, caloric restriction has been shown to improve quality of life and symptoms in HFpEF[66]. As a result, some authors have suggested that obesity and HFpEF represent different phenotype of the same disease[71] partially explaining why medications used in other forms of HF, such as RAAS inhibitors and beta-blockers, have failed to improve prognosis in HFpEF[72].

Conversely, in recent years, therapies targeting obesity pathophysiology, (i.e., glucagon-like peptide-1 receptor agonists – GLP-1RA), have demonstrated to have beneficial effects in HFpEF. In particular, GLP-1RA improve postprandial insulin response and reduce the appetite, leading to weight loss. Specifically, in obese HFpEF patients, the STEP-HFpE trial demonstrated that treatment with semaglutide led to an improvement in symptoms and physical limitations (i.e., mean change en the 6-minute walk distance and change in the quality of life, assessed by the Kansas City Cardiomyopathy Questionnaire clinical summary score - KCCQ-CSS), greater weight loss, and a significant reduction in NT-proBNP and CRP levels, with a net clinical benefit [73].

Finally, the SUMMIT-Trial showed that treatment with Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide (GIP) and Glucagon Like peptide-1 (GLP-1) receptors, led to a lower risk of a composite of death from cardiovascular causes or worsening HF than placebo and improved health status in patients with HFpEF and obesity[74,75].

Notably, GLP-1 receptor agonist may increase the risk of HF hospitalizations in HFrEF patients, as pointed out by the exploratory results based on a subgroup of the EXCEL trial (exenatide) and the FIGHT trial (liraglutide)[76]. However, recent data presented at 2024 ACC conference showed that, in a real-world scenario involving about 2000

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patients, the use of GLP-1 RA was safe and associated with better clinical outcomes[77].

All these demonstrations confirm the need to pay attention to the relationship between body fat and cardiac function, particularly in patients with clear signs of HFpEF in order to provide the most appropriate therapy; on the other hand, specific Randomized Clinical Trials are needed to further investigate the role of GLP-1RA in HFEF.

5.2. Metabolic syndrome

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors, including hyperglycemia, arterial hypertension, central obesity, hyper-triglyceridemia, and low high-density lipoproteins[78] leading to pathophysiological effects strictly connected to HF, such as endothelial dysfunction and atherogenesis, myocardial injury, increased epicardial adipose tissue (EAT) volume, cardiac remodeling, fibrosis, and throm-bosis[79]. Therefore, it is considered a risk factor for incident HF, since several observational studies showed an association between MetS and new-onset HF, especially with HFpEF[80–84]. On the other hand, MetS is highly prevalent among HF patients and portends worse clinical outcomes[85–87]. MetS is associated with a worsen hemodynamic profile, with greater elevation in cardiac filling pressures, more severe pulmonary hypertension, and greater pericardial restraint, all of which culminate in poorer exercise capacity, affecting survival[80–92]. Finally, EAT is considered a proarrhythmic substrate, associated with atrial remodeling and atrial fibrillation[93].

Therefore, addressing MetS through lifestyle modification and pharmacological interventions is critical to prevent adverse HF outcomes[94]. In this context, in the SELECT trial[95], patients with atherosclerotic cardiovascular disease and overweight or obesity but no history of diabetes treated with semaglutide had favorable HF outcomes compared to those treated with placebo; notably, this effect benefit was regardless of HF diagnosis or HF subtype. These data suggest a paradigm shift in the treatment of the metabolic phenotype of HF, potentially related to the control of MetS-related risk factors.

5.3. Diabetes mellitus

Diabetes mellitus (DM) and HF are closely bidirectionally interconnected; shared complex mechanisms have been demonstrated, involving endothelial dysfunction, metabolic derangements, neurohormonal alterations, and oxidative stress[96]. However, the diagnostic algorithm and the therapeutic approach to HF in diabetic patients is similar compared to the general HF population. Contrariwise, the treatment of diabetes in HF patients differs compared to the general population, and according to drugs efficacy and safety profile. In addition, it has been demonstrated that the primary prognostic factor in diabetic HF patients is glycaemic control throughout time, as indicated by HbA1c[97]. In this context, new antidiabetic drugs have demonstrated significant prognostic benefits in HF. For this reason, the 2021 ESC Guidelines for the management of HF[98] and its update in 2023 [99] and the 2023 ESC Guidelines for the management of CV disease in patients with diabetes[100] dedicated a specific section to diabetic HF patients, recommending the use of SGLT2 inhibitors as first-line treatment to reduce the risk of HF hospitalization or CV death. Specifically: i) Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin are recommended (class I Level of Evidence A-LoE) in patients with type 2 DM at risk of CV events to reduce hospitalizations for HF, major CV events, end-stage renal dysfunction, and CV death; ii) Dapagliflozin and empagliflozin are recommended (class I, LoE A), in all patients with HF to reduce hospitalizations for HF and CV death, regardless of ejection fraction, the presence of Type 2 DM, and independently of glycated hemoglobin levels or concomitant use of glucose lowering agents (Class I, LoE A). A different class of antidiabetic medications (i.e., GLP-1 RA), after confirming cardiovascular safety in diabetic patients, showed also benefits in terms of reduction of adverse

events in patients with atherosclerotic disease[101,102]. Therefore, regardless of baseline or target HbA1c or concomitant glucose-lowering therapy, GLP-1 RAs are now recommended for patients with type 2 DM and atherosclerotic cardiovascular disease in order to reduce cardiovascular events[100]. However, in GLP1-RA clinical trials, there was a neutral effect on HF hospitalizations. For this reason, the last released ESC Guidelines recommend the use of GLP-1 RA in diabetic HF patients just for additional glycemic control[100]. However, as previously discussed, new scenarios are now ongoing on the use of GLP1-RA in HF patients. Recently, the STEP-HFpEF DM[103] trial, conducted in DM patients, showed that semaglutide was superior to placebo in improving HF-related symptoms, quality of life (KCCQ-CSS), and exercise capacity (6MWT distance), mainly through weight loss and improvement in inflammatory and congestion biomarkers; on this basis, the STEP-HFpEF trial showed a similar effect in patients with obesity-related HFpEF, regardless of diabetes mellitus[96].

5.4. Hormonal deficiencies

A growing body of evidence showed that, complimentary to the classical pathophysiological paradigms, HF is also characterised by a concomitant reduction of anabolic and hormonal axes[104]. In particular, when two or more concomitant hormone deficiencies (HD) are detected, this condition is defined as multiple hormonal deficiency syndrome (MHDS)[105-108]. Following the preliminary results from Jankowska EA et al[101], the multicentre T.O.S.CA. registry represents the milestone on the topic, having definitely showed that more than two-thirds of HF patients are characterized with MHDS, that the presence of MHDS identifies sub-group of HF patients at increased risk of poor outcome (i.e., mortality or cardiovascular hospitalization), and that there is a graded relation between the number of HD and the adverse events. Taken all together, the presence of MHDS is associated with a worst cardiovascular performance, quality of life, and reduced survival[105,100],1071,1082.

In addition, the presence of at least a single HD was detected in about 90 % of HF patients [i.e., impairment of the somatotropic axis -growth hormone (GH) and its tissue effector insulin-like growth factor-1 (IGF-1)- anabolic steroids -testosterone and DHEA-S, thyroid hormones, and induline resistance]. The present paragraph briefly summarises the current evidence about the role of specific HD in HF and the available treatment option for these conditions[109].

5.5. Growth hormone deficiency (GHD)

It has been demonstrated that about 20–25 % of HF patients display a concomitant GHD. These patients are characterized by an impaired functional capacity and ventricular remodelling as well as worse clinical outcome[110]. Notably, GH replacement therapy in such patients demonstrated to improve HF symptoms, cardiac function, and exercise capacity, with a trend towards improvement in hard endpoints (i.e., worsening HF)[111,112]. Recently, it has been published a robust randomized, double-blind, and placebo-controlled trial demonstrating that GH replacement therapy in GHD-HFrEF patients improves exercise performance and right ventricular function, leading to an amelioration of clinical status and of health-related quality of life[113].

5.6. Testosterone (TD) deficiency

Testosterone Deficiency (TD) has been described in approximately one-third of HF patients[114,115] of both sexes. Evidence available so far point out a negative association between TD and EF, haemodynamic, and exercise capacity, leading to a worse HF outcome (i.e., mortality and hospitalisation) [114,116]; even if a proper role for the testosterone replacement therapy (TRT) in HF has not yet been full elucidated (with positive or neutral effects from small trials) [114], an overall beneficial effect of TRT in HF subjects, in particular with low basal testosterone,

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has been showed, with no safety concerns. Considering this solid path- ophysiological background, further studies are desirable [114,116].

5.7. Dysthyroidism and low T3 syndrome

Thyroid hormones (TH) have a fundamental role in cardiovascular regulation, and their perturbations (i.e., hypo- or hyperthyroidism), hugely impact on the cardiovascular system. It has been showed that both clinical$^{116}$and subclinica$^{17}$thyroid disfunction in HFrEF patients is associated with a significantly increased risk of mortality.

In addition, about one-third of HF patients display a reduction in serum biologically active serum triodothyronine (T3) levels (i.e., low T3 syndrome)[105], which is associated with a worse outcome.

5.8. Insulin resistance

Despite the well demonstrated (and previously discussed) intimate link, scarce literature is present with regard to the separate impact of Type 2 DM and Insulin Resistance (IR) on HF. Recently, the T.O.S.CA. registry showed that, when euglycemic, IR, and Type 2 DM HF patients were compared, hyperglycaemia, rather the IR, negatively affects cardiac morphology and function in HF patients; in addition, Type 2 DM HF patients display a higher degree of impairment of right ventricular function and cardiovascular performance associated with a poorer outcome [117].

6. Chronic kidney disease (CKD)

It has long been established that the heart and kidney are strictly correlated, with kidney function, necessary for water balance, being directly depending on renal blood flow and pressure generated by cardiac output. This mutual relationship is confirmed by evidence showing that kidney function deterioration is connected to the CV mortality and HF progression, while HF itself is closely associated with a more pronounced renal function deterioration [118–120]. Moreover, the progressive decline of renal function is a common feature in patients affected by HF, ranging from 23–46 % based on the study [121–128]. This decline can be due to various factors, including reduced cardiac output, venous congestion, intrarenal blood flow redistribution, endothelial and vascular alterations, neurohormonal activation, and the use of medications like diuretics [129,130]. The clinical impact of CKD in acute and chronic HF has been well established. However, larger regions and clinical trials in HF tend to exclude patients with relevant renal dysfunction despite its common prevalence in clinical practice [131,132]. Current discrepancies on CKD prevalence depends on patients' frailty, primitive disease evolution, HF stage, biventricular impairment, associated comorbidities, and inhomogeneous methods for CKD definition [133]. Commonly the renal function assessment is evaluated by the creatinine and glomerular filtration rate (GRF) values, despite additional more specific laboratory markers are commercially available allowing the evaluation of glomerular and tubular status. In clinical practice, it is difficult to recognize the prevalent pathophysiological mechanism of renal deterioration. Both biomarkers are able to identify late renal damage, but ineffective to recognize early stage of WRF as well as tubular or glomerular damage [134]. Consequently, physicians are unable to identify the specific hemodynamic or intrarenal mechanisms responsible for deterioration.

Notably a recent post hoc analysis of PARADIGM-HF trial based on dividing patients according to KDIGO classification, showed that subjects with the worst renal function experienced the highest rates of the primary composite outcome [135]. Due to relevant discrepancies among studies regarding prevalence and related prognostic consequences, a more detailed investigation on renal function assessment across time in patients affected by HF appears crucial to better understand the real impact as well as the natural history of patients with both HF and CKD. Indeed, most existing findings derive from post hoc analysis or

interventional trials including patients with different clinical status, LVEF values, and renal disease [129,136]. For these reasons, specific studies evaluating cardiac and renal endpoints in HF patients with concomitant CKD are a priority to better comprise the exact risk burden and clinical significance.

7. Potassium disorders

Potassium disorders (i.e., hypokalemia and hyperkalemia) in HF are common, linked to HF per se, related comorbidities impacting on potassium balance (e.g., chronic kidney diseases), and HF medications affecting potassium levels (i.e., RAAS inhibitors) [137].

Whereas the relationship between potassium concentrations and adverse outcomes appears to be U-shaped, the potassium safe zone is not well established [137].

7.1. Hyperkalemia

Hyperkalemia, defined as a serum potassium concentration exceeding 5.0 mmol/L, is a frequent and clinically relevant electrolyte imbalance in patients with HF, with a reported prevalence ranging from 7 % to 39 % [138]. It is categorized as mild (<5.9 mmol/L), moderate (6–6.5 mmol/L), and severe (>6.5 mmol/L).

Hyperkalemia is particularly common in individuals with advanced HF, CKD, and those undergoing treatment with RAAS inhibitors, mineralocorticoid receptor antagonists (MRA), or potassium-sparing diuretics. Additional risk factors include older age, male gender, diabetes, and hypertension, all of which necessitate vigilant monitoring [139]. While elevated serum potassium levels do not directly increase the risk of cardiovascular events – except for ventricular arrhythmia – they often result in the reduction or discontinuation of RAAS inhibitor therapy, which is associated with poorer prognosis, including increased mortality and HF hospitalizations [140]. Managing hyperkalemia in HF patients requires a multifaceted approach, including dietary potassium restriction, careful titration of RAAS inhibitors, and the use of potassium binders such as patiromer or sodium zirconium cyclosilicate. Many randomized controlled trials demonstrated that potassium binders effectively reduce serum potassium levels and the risk of hyperkalemia [141–143], thereby allowing for higher RAAS inhibitor dosages in patients with HFrEF without increasing adverse events.

7.2. Hypokalemia

Hypokalemia, defined as a serum potassium concentration below 3.5 mmol/L, despite being frequent and clinically relevant in patients with HF-prevalence of about 20 % of HF patients- remains a much neglected condition [137]. It is classified as mild (3.0–3.5 mmol/L), moderate (2.5–3 mmol/L), and severe (<2.5 mmol/L). Notably, about 4 % of patients with hypokalemia experience at least an event of severe hypokalemia

However, whereas the association between poor outcomes and moderate to severe hyperkalemia has been well-established, the role of hypokalemia is still debatable [137]. For instance, on the one hand, results from observational studies and clinical trials indicate that hypokalemia is associated with increased morbidity and mortality [144]; on the other hand, more recent and focused analyses showed that while hyperkalemia was clearly associated with increased 30-days mortality [145] and all-cause mortality [146], hypokalemia was not [145,146]

Finally, there is still debate whether the association between hypokalemia and poor outcomes should be directly attributed to hypokalemia (namely, causative) or whether hypokalemia represents just a marker for more advanced and serious patients (namely, reverse causation) [137]

Therefore, overall, available evidence suggests that hypokalemia can be considered at least, as detrimental [147] and strategies in maintaining serum potassium levels within the normal range should be

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pursued (i.e., stop thiazides, start or increase MRA, increase RAAS inhibitors, potassium supplement if necessary); however, no definitive evidence is available about a causative effect [137].

8. Cardiac cachexia

Cardiac cachexia, characterized by involuntary weight loss, is typically recognized in patients with stage D (advanced) HF [148,149]. It is defined as an unintentional edema-free weight loss of more than 5-6 % over at least 6 months with the following criteria: 1) decreased muscle strength, 2) fatigue, 3) anorexia, 4) low fat free mass index, and 5) abnormal biochemistry [anaemia (Hb<120 g/L), low serum albumin (<32 g/L), increased inflammatory markers (CRP >5mg/L, IL-6 > 4pg/mL). With a prevalence ranging from 5 % to 15 %, cardiac cachexia is related with worse prognosis [150–152]. Cardiac cachexia in HF represents the final evolution of sarcopenia, leading to the loss of both skeletal muscles mass and fat mass. This process encompasses various pathophysiological mechanisms, such as mitochondrial dysfunction due to hypoxia -which leads to the changes in muscle fiber structure and subsequent atrophy-, and high inflammation status, caused by the increased cytokine levels, the increased oxidative stress, and the resulting protein degradation. Together with these structural alterations, the chronic cardiac and venous congestion are related to renal and bowel congestion which leads to increased circulating toxins and malabsorption syndrome [148,153–160].

Despite the well-known association between cardiac cachexia and poor prognosis in HF patients [161–163], there are currently no specific treatments to interrupt the progression from sarcopenia to cachexia. However, this pathological condition should be included in the definition of advanced HF and should be investigated in patients submitted to heart transplantation or mechanical circulatory support, in order to evaluate the possible interruption of this pathological derangement.

9. Anaemia and iron deficiency (ID)

Anaemia is a frequent comorbidity in subjects affected by HF [164, 165]. From a pathophysiological point of view, it results from of a complex multifactorial interaction (iron deficiency, kidney disease, nutritional deficiencies, gastrointestinal bleeding, and cytokine production). It has been associated with a significantly increased risk of hospital admissions and CV mortality. However, after the neutral results of the RED-HF trial [166] (i.e., increasing HGB to 12-13 g/dL by erythropoietin does not improve outcomes in HF patients with anemia) the focus shifted to the role of iron deficiency.

According to guidelines, iron deficiency is diagnosed when ferritin levels are below 100 µg/L or when transferrin saturation is less than 20 % [98,167], with ferritin levels ranging between 100 and 300 µg/L. Therefore, ID can be characterized either by a reduction in iron stores (low ferritin levels) or by impaired iron transport (transferrin saturation <20, irrespective of ferritin levels). Iron transport deficiency is common in both HFrEF and HFpEF and is associated with worsening clinical outcomes [165].

From an epidemiological perspective, iron deficiency in chronic HF can be present regardless of anaemia [169] and tends to worsen during disease exacerbations [170]. The most frequent causes of iron deficiency in HF are malabsorption or intestinal losses. Since iron is a crucial element for both haemoglobin synthesis and many oxidative-reductive processes in the mitochondrial respiratory chain - due to its ability to exist in both oxidized (Fe$^{3+}$) and reduced (Fe$^{2+}$) forms - its deficiency can lead to anaemia as well as downregulation of various enzymatic activities [171]. ID is more common in patients with HFPr, which is associated with reduced functional capacity, evident through decreased oxygen consumption and ventilation efficiency [172,173], and worsened prognosis and mortality [174]. In patients with HFpEF, ID leads to reduced functional capacity [175], increased oxidative stress, and a heightened inflammatory status [176].

Based on the results from most recent trials (i.e., FAIR-HF, CONFIRM-HF, EFFECT-HF, AFFIRM-AHF, and IRON MAN trials), guidelines recommend intravenous iron supplementation in symptomatic patients with HFrEF and HFmrEF and iron deficiency, to alleviate HF symptoms and improve quality of life (Class I LoE A), and to reduce the risk of HF hospitalization (Class Ia LoE A) [177,178]. After guidelines publication, results from the HEART FID trial and from the FAIR-HF2 trial are available, with less than encouraging results; indeed, both trials failed to show any difference with respect to the hierarchical composite of death, hospitalizations for HF, or 6-minute walk distance [179] or to reduction in each of the three primary outcomes (time to cardiovascular death or first HF hospitalization, total HF hospitalizations, time to cardiovascular death or first HF hospitalization in patients with low transferrin saturation) [180]. However, data from a subsequent metanalyses, including also these 2 trials, confirmed that treating iron deficiency in patients with HFrEF significantly reduces the composite outcome of recurrent HF hospitalizations and cardiovascular mortality, (mostly driven by HF hospitalizations); in addition, treatment effects were more evident in the first year after and consistent across various subgroups, including baseline levels of the transferrin saturation [181].

10. Neuropsychiatric disorders

10.1. Depression

Depression and anxiety disorders in HF represent a major health problem, reaching up to 20 % of subjects, with higher involvement in the female sex, and are associated with a worse prognosis and severe impairment of quality of life [182,183], with an increased risk of death or rehospitalization within 3 to 12 months after HF hospitalization. Therefore, the evaluation of depressive disorder should be included in the multidisciplinary assessment of HF patients through the use of tools like the Beck Depression Inventory and Cardiac Depression Scale [184]. Among therapies available, the first approach includes pharmacotherapy, psychotherapy, and exercise. Some trials have demonstrated that cognitive behavioural therapy (CBT) impacts quality of life but does not improve prognosis. Trials based on the use of antidepressant drugs, such as the SADHART-CHF trial [185] with sertraline, or the MOOD-HF trial [186] with escitalopram, have not shown a clear benefit on prognosis; however, a significant improvement of depressive symptoms are reported. Notably, the use of tricyclic antidepressants is contraindicated in HF, for collateral effects such as hypotension, arrhythmias, and worsening HF [187].

10.2. Cognitive impairment

The progressive ageing of society determines the increased prevalence of cognitive impairment (CI), currently affecting about 40 % of the HF population [188]; in addition, HF increases of 2-fold the risk of CI, likely due to cerebral hypoperfusion and flow dysregulation [189]. The consequent alteration of neurological activities determines a worse prognosis, in terms of mortality and hospitalization, and can also lead to a low HF medication adherence [190].

Clinicians should administer tests to recognize and monitor CI, such as Mini-Mental State Examination (MMSE) and Mini-Cog [190] as reported in the 2016 European guidelines of HF[40] and recent American Statements$^{191}$. However, the newer 2021 European HF guidelines do not mention these tools for assesment[98]. To date, any therapeutic strategy has been able to improve cognition or prevent CI progression in HF patients.

11. Gaps in evidence and future perspectives

11.1. Gaps in evidence and future perspectives

Even though several advances have been made in the field, there is

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still limited understanding about the optimal management of noncardiovascular comorbidities in HF. The present working group identified several gaps in evidence in need of future further investigations. Specifically:

1. Sleep-Disordered Breathing: even if treatments (e.g., CPAP for OSAS) do exist, none of them have yet consistently shown beneficial effects on HF outcomes for Central Sleep Apnea (CSA), in particular in HFrEF.

2. Chronic Obstructive Pulmonary Disease (COPD): clear evidence on the safety of long-acting β2-agonists as bronchodilators in HF patients is still lacking, even though their use represents an established treatment of this condition.

3. Cardiac cachexia: no specific treatment has been yet identified to counteract its progression, especially in patients with advanced HF who are candidate to heart transplantation or mechanical circulatory support.

4. Cognitive impairment: there is currently no specific therapeutic strategy available in HF patients.

5. Chronic Kidney Disease (CKD): patients with advanced renal dysfunction are underrepresented in clinical trials, so that specific studies evaluating cardiac and renal endpoints in HF patients with concomitant renal disease are a priority. Also, the safety and extension of actual prescription of GDMT to HF patients who are also affected by CKD currently represents a matter of interest of the scientific community, given its high frequency and poor prognosis.

6. Iron deficiency: the diagnosis of iron deficiency is currently based on specific ferritin and transferrin saturation (TSAT) levels, but the nuances of iron transport versus iron storage deficiency and their distinct impacts remain objects of ongoing studies and of fervent debates, while its definition has already been questioned and will possibly be updated in the next years. In addition, the role of oral iron supplementation has not been yet established.

7. Diabetes mellitus: new scenarios are emerging for the use of GLP-1 receptor agonists and derived compounds, extending potentially beyond diabetic status, while new therapeutic frontiers may emerge.

8. Hormone deficiencies: despite the most recent findings about hormonal deficiencies, including the possible use of testosterone and growth hormone replacement therapy in HF patients, the proper role has not yet been fully elucidated, and further studies are desirable to confirm its beneficial effects.

Overall, non-CV comorbidities represent a significant challenge for healthcare professionals and an emerging target for novel HF treatments, underscoring the need for a multidisciplinary and tailored approach to improve patient outcomes.

11.2. Future perspectives: multidisciplinary approach

A multidisciplinary approach has been advocated as the most promising and useful strategy to adopt for a correct management of HF patients [98,167]. Indeed, it has been demonstrated that multidisciplinary management reduces hospitalization and mortality, allowing patients to undergo accurate investigations, have a correct diagnosis, and an appropriate follow-up; as a result, it is recommended in Class I LoE A in the latest guidelines [98,167]. The present panel of experts strongly supports this recommendation, also considering that, because of the burden of comorbidity faced by HF patients in the recent years, the HF management has become more complex; therefore, there is an urgent need to integrate the classic HF specialist unit (based on general HF, LVAD, and heart transplant services) with several other specialies able to manage all the non-CV comorbidities (e.g., internal medicine specialists, endocrinologists, pulmonologists, nephrologists, oncologists) [191]. In addition, establishing appropriate integration between the HF specialist units and the primary care is imperative, as the first approach to the patient often occurs performed in the primary care setting [191]. Finally, the role of non-physicians (e.g., nurses, physiotherapists, nutritionists, psychologists) and non-clinical health care

workers (e.g., community health workers, medical secretaries, medical transcriptionists, and medical administrative assistants) should be considered, and the education of these workers should be prioritized [192].

12. Conclusion

Non-CV comorbidities are very common in HF and represent a challenge for physicians and researchers in the field of HF. In addition, non-CV comorbidities represent an emerging target for HF treatment, with promising results from recent trials.

A multidisciplinary approach for the management of non-CV comorobidities in HF is needed, considering that such non-CV comorbidities may negatively impact the prognosis of HF patients, and vice-versa HF exacerbations may worsen non-CV concomitant clinical conditions.

Declaration of competing interest

The authors declare they have no conflict of interest (in particular, the Italian Society of Cardiology (ISC) Working Group on Heart Failure has not received funding from the pharmaceutical industry).

Acknowledgments

Italian Society of Cardiology (ISC) Working Group on Heart Failure: Giuseppe Ambrosio (Cardiology and Cardiovascular Pathophysiology, S. Maria Della Misericordia Hospital, University of Perugia, Perugia, Italy), Italy), Attentional Medical Sciences, University of Naples Federico II, Naples, Italy), Giuseppe Armentaro (Geriatrics Division, "Renato Dulbecco" University Hospital of Catalanzaro, Catanzaro, Italy), Roberto Badagliacca (Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, 'Sapienza' University of Rome, Policlinico 'Umberto I' of Rome, Rome, Italy.), Matteo Beltrami (Arrhythmia and Electrophysiology Unit, Careggi University Hospital, 50134 Florence, Italy; Cardiomyopathy Unit, Careggi University Hospital 50134 Florence, Italy), Maria Cristina Carella (Cardiology Unit, Interdisciplinary Department of Medicine, Italy), Erberto Carluccio (Cardiology and Cardiovascular Pathophysiology, S. Maria Della Misericordia Hospital, University of Perugia, Perugia, Italy), Michele Ciccarelli (Department of Medicine, Surgery and Dentistry, University of Salerno, Bari, Italy), Maria francesca Marco Matteo Ciccone (Cardiology Unit, Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Bari, Italy), Maria francesca Di Santo (Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy), Francesco Fioretti (Section of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy), Stefano Ghio (Division of Cardiology, Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia, Italy), Francesco Loria (Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy), Damiano Magri (Department of Clinical and Molecular Medicine, University "La Sapienza," Rome, Italy), Alberto Maria Marra (Department of Translational Medical Sciences, Federico II University, Naples, Italy) Gianfranco Parati (Department of Cardiology, San Luca Hospital, Istituto Auxologico Italiano, ICICS, Milan, Italy & School of Medicine and Surgery, Milano-Bicococa University, Milan, Italy), Carlo Gabriele Tocchetti (Department of Translational Medical Sciences, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples, Italy), Carmine Dario Vizza (Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, 'Sapienza' University of Rome, Policlinico 'Umberto I' of Rome, Rome, Italy) Dr Giulia Crisci has received a research grant from the CardioPath program from Federico II University of Naples, Italy.

versity of Rome, Policlinico 'Umberto I' of Rome, Rome, Italy.), Matteo Beltrami (Arrhythmia and Electrophysiology Unit, Careggi University Hospital, 50134 Florence, Italy; Cardiomyopathy Unit, Careggi University Hospital 50134 Florence, Italy), Maria Cristina Carella (Cardiology Unit, Interdisciplinary Department of Medicine, University of Bari Aldo

Moro, Bari, Italy), Erbert Carluccio (Cardiology and Cardiovascular Pathophysiology, S. Maria Della Misericordia Hospital, University of Perugia, Perugia, Italy), Michele Ciccarelli (Department of Medicine, Surgery and Dentistry, University of Salerno, Bari, Italy), Maria francesca Marco Matteo Ciccone (Cardiology Unit, Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Doro, Bari, Italy), Maria francesca

Di Santo (Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy), Francesco Fioretti (Section of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy), Stefano Gio (Division of Cardiology, Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia, Italy), Francesco Loria (Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy), Damiano Magri (Department of Clinical and Molecular Medicine, University "La Sapienza," Rome, Italy), Alberto Maria Marra (Department of Translational Medical Sciences, Federico II University, Naples, Italy) Gianfranco Parati (Department of Cardiology, San Luca Hospital, Istituto Auxologico Italiano, ICICS, Milan, Italy & School of Medicine and Surgery, Milano-Bicococa University, Milan, Italy), Carlo Gabriele Tocchetti (Department of Translational Medical Sciences, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples, Italy), Carmine Dario Vizza (Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, 'Sapienza' University of Rome, Policlinico 'Umberto I' of Rome, Rome, Italy) Dr Giulia Crisci has received a research grant from the CardioPath program from Federico II University of Naples, Italy.

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