{"paper_id":"28dbdc32-d8dd-4dd0-ab0e-aaa1a56ccc34","body_text":"Unwanted loneliness in heart failure: risk factors and association with prognosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Unwanted loneliness in heart failure: risk factors and association with prognosis Teresa Benito, Georgiana Zaharia, Adora Pérez, Cristina Jaramillo, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4574185/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Sep, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Introduction and Objectives: Heart failure (HF) is associated with a high prevalence of unwanted loneliness. This study aimed to assess the risk factors associated with unwanted loneliness and its association with the risk of adverse clinical events in a cohort of patients with HF. Methods: We included 298 patients diagnosed with stable HF. Clinical, biochemical, echocardiographic parameters and loneliness using ESTE II scale were assessed. We analyzed risk factors using multivariate logistic regression. We evaluated the association with the risk of recurrent all-cause admissions using negative binomial regression accounting for the risk of death. Results: The mean age was 75.8±9.4 years, with 111 (37.2%) being women, 53 (17.8%) widowed, and 154 (51.7%) patients having preserved ejection fraction. The median (p25% - p75%) ESTE II score was 9.0 (6.0 – 12.0), and 36.9% experienced loneliness. Both women (OR=2.09; 95% CI: 1.11 to 3.98, p=0.023) and widowhood (OR=3.25; 95% CI: 1.51 to 7.01, p=0.003) were associated with a higher risk of loneliness. During follow-up, loneliness was significantly associated with increased all-cause hospitalizations (IRR=2.05; 95% CI: 1.24-3.40, p=0.005). Conclusions: Women and widowhood emerge as risk factors for unwanted loneliness in HF patients. Unwanted loneliness is associated with higher morbidity during follow-up. Health sciences/Cardiology/Cardiovascular biology Health sciences/Risk factors Unwanted Loneliness Heart Failure Widowhood Women Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Heart failure (HF) is a clinical syndrome with a high and increasing prevalence 1 . In addition to its high morbidity and mortality, recent studies in North American and Central European populations suggest that, in chronic pathologies such as HF, unwanted loneliness is common 2,3 . However, the factors associated are not well defined, particularly in our environment. Furthermore, the evidence on its clinical repercussions is limited and, in many cases, heterogeneous 4,5 . Biological, psychological and social factors could underline behind the deleterious consequences of unwanted loneliness on health. In this manner, we speculate that unwanted loneliness could be associated with a higher risk of adverse clinical events. In the present study, we sought to evaluate the factors associated with the presence of unwanted loneliness, and the association of this presence with the risk of presenting adverse clinical episodes during follow-up in a population with chronic HF in our environment. METHODS Study population and procedures We conducted a single-center, cross-sectional, prospective observational study including an unselected cohort of patients meeting the HF criteria, according to the European Society of Cardiology Guidelines 2021 6 . The study sample consisted of consecutive patients who attended the Heart Failure Unit of the Cardiology Service of the Hospital Clínico Universitario of Valencia from May 2022 to July 2022 and agreed to participate. Patients were included regardless of left ventricular ejection fraction (LVEF). During the baseline visit, we collected demographic data (age, sex), clinical data (weight, edema, jugular venous distention, body mass index, and medical history), vital signs (heart rate, systolic and diastolic blood pressure, oxygen saturation), electrocardiogram, and laboratory parameters (NT-proBNP, CA125, urea, creatinine, uric acid, sodium, potassium, and hemoglobin), echocardiographic values (LVEF), and pharmacological treatment. We obtained demographic, clinical, and analytical parameters on the same day as the loneliness questionnaire results. Echocardiographic parameters were extracted from the patient's medical history, using values closest to the baseline visit. Assessment of unwanted loneliness We evaluated unwanted loneliness using the validated ESTE II questionnaire 7 . This questionnaire evaluates unwanted loneliness considering three factors including the perception of social support, the use of new technologies and the subjective social participation index. The questions that underlie each of the questionnaire factors are reflected in Fig. 1 . The total score ranges between 0 and 30, with higher scores indicating greater loneliness. Based on the score obtained in each of the responses, we classified patients into three established levels of unwanted loneliness 7 : low (0–10), medium ( 11 – 20 ) and high (21–30). Clinical endpoints Follow-up and Endpoints We recorded all-cause admissions and all-cause urgent visits during the follow-up. The primary endpoint was the incidence of all-cause hospitalizations and the composite of all-cause admissions or visits to the emergency department during follow-up. Similarly, we evaluated the time to the first event of the combined death/admission for all causes. We defined admission as any unscheduled hospital stay > 24 hours and emergency visits as unplanned visits ≤ 24 hours. The personnel in charge of endpoint adjudications were blinded to the grade of unwanted loneliness survey. Statistical analysis We expressed continuous variables as mean ± standard deviation or median (25% percentile − 75% percentile), as appropriate. We presented categorical variables as percentages. We evaluated differences between baseline variables and unwanted loneliness using the chi-square test for categorical variables and T-test or Kruskal-Wallis test for continuous variables. We used logistic and multiple linear regressions to evaluate risk factors associated with loneliness (ESTE score > 10) and the continuous ESTE score, respectively. We present results as odds ratios (OR) and β coefficients, respectively. We analyzed the contribution of covariates to the final multivariate logistic regression model's variability using the coefficient of determination (R2). For recurrent events (all events during follow-up: all-cause hospitalizations, emergency visits, or death), we used negative binomial regression and presented risk differences as incidence rate ratios (IRR). We used multivariate Cox regression to examine the association between loneliness and time to the first adverse event, presenting results as hazard ratios (HR). We selected covariates in multivariate models based on biological plausibility, regardless of p-value. The final prognostic multivariate models included a set of 10 covariates: age (years), female (yes/no), widowed (yes/no), New York Heart Association (NYHA) functional class (≥ 3), LVEF (% ), previous history of Acute Myocardial Infarction (AMI) (yes/no), type 2 DM (yes/no), previous history of stroke (yes/no), cancer (yes/no) and NT-proBNP (pg/ ml). We conducted all analyses with: STATA 16.1 [Stata Statistical Software, Release 16 (2019); StataCorp LP, College Station, TX, USA]. Ethics statement The Ethics Committee of the Hospital Clínico Universitario of Valencia approved the study in accordance with the principles of the Declaration of Helsinki. All patients gave their informed consent. RESULTS Basal characteristics The mean age of the sample was 75.8 ± 9.4 years, 111 (37.2%) were women, 53 (17.8%) were widows, 154 (51.7%) showed heart failure with preserved LVEF, and 260 (87.2%) were in stable NYHA II functional class. The median value (p25% - p75%) of the ESTE II score was 9.0 (6.0–12.0) and 36.9% showed unwanted loneliness > 10. Subjects with unwanted loneliness were older [79.0 (72.0–86.0) vs. 75.0 (67.0–81.0), p < 0.001]; more frequently women [63 (54.8%) vs. 52 (45.2%), p < 0.001]; and more were in a state of widowhood [38 (33.0%) vs. 15 (8.2%), p < 0.001]. Regarding clinical variables, unwanted loneliness was more frequent in patients with NYHA III/IV functional class [15 (13.1% vs. 14 (7.7%), p = 0.032]), also showing lower weight [73 .1 (63.4–85.3) vs. 76.8 (70.7–88.9), p = 0.011]; worse estimated glomerular filtration rate [49.6 (37.1–61.8) vs. 55.9 (38.9–75.2), p = 0.017]; and less history of AMI [10 (8.7%) vs 41 (22.4%), p = 0.002]. The baseline characteristics of the population according to the presence of unwanted loneliness are shown in Table 1 . Table 1 Basaline characteristics. Variables Alone Not alone All p-value n 115 183 298 Demographics and previous medical history Age, years 79.0 (72.0- 86.0) 75.0 (67.0- 81.0) 76.5 (69.0- 84.0) < 0.001 Loneliness, score 13.0 (12.0–16.0) 7.0 (5.0–9.0) 9.0 (6.0–12.0) < 0.001 Female, n (%) 63 (54.8) 48 (26.2) 111 (37.2) < 0.001 Widow, n (%) 38 (33.0) 15 (8.2) 53 (17.8) < 0.001 BMI, Kg/m^2 28.3 (24.8–32.3) 27.9 (25.0-31.1) 28.1 (25.0-31.2) 0.704 Hypertension, n (%) 83 (72.2) 132 (72.1) 215 (72.1) 0.994 Mellitus Diabetes, n (%) 53 (46.1) 80 (43.7) 133 (44.6) 0.428 Dyslipidemia, n (%) 60 (52.2) 96(52.5) 156 (52,3) 0.962 Previous history of AMI, n (%) 10 (8.7) 41(22.4) 51 (17.1) 0.002 Previous history of stroke, n (%) 3 (2.6) 13 (7.1) 16 (5.4) 0.094 History of cancer, n (%) 9 (7.8) 9 (4.9) 18 (6.0) 0.305 NYHA III//IV, n (%) 15 (13.1) 14 (7.7) 29 (9.7) 0.032 Vital Signs and ECG Heart rate, bpm. 71.0 (6.0- 78.0) 71.0 (61.0- 80.0) 71.0 (62.0- 74.0) 0.538 Systolic blood pressure, mmHg 125.0 (112.0-140.0) 125.0 (111.0- 139.0) 125.0 (112.0- 139.0) 0.781 Diastolic blood pressure, mmHg 66.0 (60.0–75.0) 68.0 (61.0–74.0) 67.0 (60.0–74.0) 0.666 Atrial fibrillation, (%) 54 (47.0) 82 (44.2) 136 (45.6) 0.717 Laboratory values Hemoglobin, g/dL 13.5 (12.2–14.7) 14.0 (12.5–15.2) 13.8 (12.4–15.0) 0.062 GFR CDK-EPI, mL/min/1,73m2 49.6 (37.1–61.8) 55.9 (38.9–75.2) 51.8 (38.2–72.3) 0.017 Sodium, mEq/L 140.0 (138.0-141.0) 140.0 (138.0-142.0) 140.0 (138.0-142.0) 0.198 NT-proBNP, pg/mL 1275.0 (545.0- 2167.0) 947.0 (372.0- 2485.0) 1073.5 (404.0- 2225.0) 0.266 CA125, U/mL 16.0 (10.0–22.0) 13.0 (9.0–19.0) 13.0 (9.0–21.0) 0.569 Echocardiography LVEF, % 53.0 (41.0- 60.0) 48.0 (38.0- 58.0) 50.0 (39.0- 59.0) 0.071 Medical treatment Diuretics, n (%) 101 (87.8) 152 (83.1) 253 (84.9) 0.263 ARNI, n (%) 40 (34.8) 72 (39.3) 112 (37.6) 0.429 ARB, n (%) 21 (18.3) 32 (17.5) 53 (17.8) 0.865 MRA, n (%) 59 (51.3) 80 (43.7) 139 (46.6) 0.201 β-blockers, n (%) 82 (71.3) 140 (76.5) 222 (74.5) 0.316 ARB: angiotensin II receptor blockers; MRA: mineralocorticoid receptor antagonists; CA125: carbohydrate antigen 125; LVEF: left ventricular ejection fraction; BMI: body mass index; ARNI: angiotensin receptor–neprilysin inhibitor; bpm: beats per minute; GFR: glomerular filtration rate; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association . Risk factors associated with loneliness The independent factors associated with the presence of unwanted loneliness were female sex (OR = 2.09; 95% CI: 1.11 to 3.98, p = 0.023) and widowhood (OR = 3.25; 95% CI: %:1.51 to 7.01, p = 0.003). On the contrary, a history of previous AMI showed as a protective factor (OR = 0.39; 95% CI:0.17 to 0.89, p = 0.025). Variables related to the severity of HF such as NYHA functional class (p = 0.293), comorbidities [DM (p = 0.095) and stroke (p = 0.073)], LVEF (p = 0.488), NT-proBNP (p = 0.248) and glomerular filtration rate (p = 0.398), were not associated with the risk of loneliness. In the analysis of ESTE II score as a continuous variable, multiple linear regression showed that both women (β coefficient = 2.25; 95% CI: 0.88 to 3.62, p = 0.001) and widowhood (β coefficient = 1.96; 95% CI:0.33 to 3.58, p = 0.018) were significantly and positively associated with the ESTE II score (Fig. 2 a and 2 b, respectively). On the contrary, the previous history of AMI was once again a protective factor (β-coefficient=-1.55; 95% CI: -3.03 to -0.78, p = 0.039) (Fig. 2 c). Age showed a positively and numerically association with the ESTE score; however, this association did not reach statistical significance (β-coefficient = 0.05; 95% CI: -0.01 to 0.12, p = 0.115). Unwanted loneliness: relation with recurring admissions and visits to the emergency room During a median (p25%-p75%) follow-up of 362 days (323–384), 22 (7.4%) deaths, we recorded 22 deaths (7.4%), 102 hospitalizations in 84 patients (28.3%), and 391 all-cause hospitalizations or emergency visits in 168 patients (56.4%). HF caused a total of 34 hospitalizations in 27 patients. The rate of admission for all causes was significantly higher in those with unwanted loneliness (6.7 vs. 4.4 per 10 person-years, p = 0.031). These risk differences were maintained after multivariate adjustment. Thus, unwanted loneliness doubled the risk of admission for all causes (IRR = 2.05; 95% CI: 1.24–3.40, p = 0.005). When we evaluated the association between self-perceived loneliness and the adverse episode composed of all admissions or visits to the emergency room, it corroborated once again that those subjects with loneliness presented higher rates (16.3 vs. 12.9 per 10 person-year, p = 0.029). This increased risk was also maintained after multivariate analysis (IRR = 1.42; 95% CI: 1.02–1.96, p = 0.037). Unwanted loneliness and morbimortality risk During follow-up, 93 patients (31.3%) presented the combined episode of death or all-cause admissions. The risk of this combined episode was higher in those with self-perceived loneliness (5.1 vs 3.3 per 10-person-year, p = 0.021), with differences that increased progressively throughout follow-up (Fig. 3 ). Multivariate Cox regression confirmed that unwanted loneliness increased the risk of dying or being admitted for any cause (HR = 1.83; 95% CI: 1.18 to 2.84, p = 0.007). DISCUSSION In this study, we found that in patients with HF, female sex and widowhood are factors associated with unwanted loneliness, while a history of AMI appears as a protective factor. It also confirms that self-perceived loneliness associates with greater risk of poor prognosis during follow-up. From Sullivan's 8 definition to the present, loneliness has gained relevance as a risk factor that contributes negatively to mental health, physical health, health behavior, and the risk of death 5,9,10 . Simultaneously, concepts related to loneliness have been narrowed down (including loneliness and social isolation) and multiple scales have been developed for research 11 . Although not universally adopted, the WHO defines “loneliness” as a painful subjective feeling – “social pain” – resulting from a discrepancy between desired and actual social connections, and “social isolation” as the state goal of having a small network of family and non-family relationships and, therefore, few or infrequent interactions with others 5 . The ESTE II Social Loneliness Scale was developed and validated at the University of Granada in our country in 2009 and delves into social loneliness understood as the perception and experience that a subject has in relation to their membership in a social network 7 . Loneliness in HF: previous evidence The association between loneliness-social isolation and health deterioration is bidirectional 12,13 . Most studies linking unwanted loneliness and HF have focused on investigating the role of loneliness and/or social isolation as a risk factor for developing HF. There is a consistent association between loneliness and/or social isolation with coronary heart disease 14–16 , however, the evidence for an association between unwanted loneliness and the development of HF is limited and inconclusive, probably due to heterogeneity in the definition of loneliness. A prospective study of a cohort of men between 60 and 79 years selected from General Practice clinics in 24 British cities stated that low social contact increased the risk of HF 17 . Cené et al. showed that social isolation increased the risk of HF independently of traditional cardiovascular risk factors in a cohort of postmenopausal women without a previous diagnosis of HF from the Women's Health Initiative 4 . Similarly, in a population cohort extracted from the UK Biobank database, Liang et al. concluded that loneliness and social isolation are independently associated with the development of HF regardless of genetic risk 18 . The scientific literature related to unwanted loneliness and the factors associated with patients already diagnosed with HF is also scarce. In our study, the percentage of loneliness in patients with HF was 36.9%. Previous studies show quite different figures for unwanted loneliness, between 20% and 78% 19–21 . Presence of medium-high grade of loneliness was more homogeneous (20–25%) with validated sacles 19,20 than when loneliness was measured with non-validated scales (78%) 21 . In Spain, the prevalence of unwanted loneliness in people aged 65 or older is 20%, being slightly higher in women 22 . The high prevalence in our study could be due to many reasons: a) the type of the scale used; b) older age; c) the chronic nature of HF; d) the size of the sample; and e) the subgroup of the population studied. 23,24,25 . The present results show that loneliness in patients with HF is associated with female sex (a result that agrees with the rest of the studies in patients with HF) 19–21 and with widowhood. The widowhood has not usually been evaluated in this particular context. However, previous studies suggest that, in patients with HF, being married 20 or living with someone 19 is shown to be a protective factor for the development of social isolation or loneliness. In the same sense, living alone was a risk factor for the development of loneliness in multi-pathological patients over 50 years of age in Southeastern Europe 26 . What stands out in our study is the result that links a history of AMI as a protective factor for the presence of unwanted loneliness in patients with HF. Previous studies have not shown any relationship between a history of ischemic heart disease and loneliness in this patient profile 19,20 . As mentioned previously, loneliness is a risk factor for the development of ischemic heart disease and has been equated to other traditional cardiovascular risk factors such as obesity and smoking 10 . It is therefore striking that, in our study, a history of AMI is shown as a protective factor for the development of loneliness. The reasons explaining this association are elusive; however, we speculate that the story of AMI culturally resonates as a serious situation. This is why perhaps the people closest to the patient with previous AMI increase their ties to them, thus decreasing the perception of loneliness. Furthermore, patients with ischemic heart disease appear to be the main beneficiaries of cardiac rehabilitation programs that, at least initially, increase social contact. Prognostic implications: the importance of measuring unwanted loneliness in HF The increase in visits to the emergency room, hospitalization, addition in days of hospitalization, and consumption of other health resources in patients with unwanted loneliness in different clinical scenarios has been demonstrated on several occasions since the original study by Gellers et al. 10,19,20,22 . Regarding the increase in mortality, a recent meta-analysis 27 concluded that, in general population, loneliness and social isolation were significantly associated with an increased risk of all-cause death, and that social isolation also increased mortality for all causes in individuals with cardiovascular disease. In this manner, the present results seem to confirm the association between unwanted loneliness and worse clinical outcomes already observed in different clinical contexts. The present work confirms the high prevalence of unwanted loneliness in HF, but also adds novel and relevant information about its clinical consequences. Specifically, this is the first work to show that unwanted loneliness in our country could be associated with a greater risk of adverse clinical events in patients with established HF. The causes that explain the association between unwanted loneliness and poorer clinical outcomes in HF seem to be multifactorial, among which we see: a) greater anxiety and stress due to symptoms, b) unhealthy lifestyle habits, c) lack of therapeutic adherence, and d) biological factors. Given its high prevalence and repercussions, it seems sensible to suggest that the evaluation of unwanted loneliness should be done more routinely in the HF care setting. In this way, the identification of the most vulnerable patients could be followed by a closer clinical approach and possibly implement social/psychological intervention strategies that seek to mitigate or reduce the feeling of loneliness. The contribution of improving loneliness in patients with HF to well-being seems feasible. However, how these can contribute to better care and the achievement of better clinical results deserves to be the subject of prospective studies dedicated to this. Limitations Several limitations in this study must be acknowledged. Firstly, this is an observational study in which numerous confounding factors may be operating. Second, this is a study carried out in a single center and there may be a selection bias that makes it difficult to extrapolate results to other settings. Third, this study is not designed to understand the social/cultural/psychological/biological mechanisms behind the present findings. Fourth, the power of the present study does not allow us to evaluate clinical adverse events such as mortality in isolation and specific readmissions due to HF. CONCLUSIONS In this contemporary cohort of outpatients with HF, a high prevalence of unwanted loneliness is confirmed, which is more common in women and widows. Its presence is associated with worse clinical outcomes during follow-up. DATA AVAILABILITY The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Abbreviations CA125 Carbohydrate antigen 125 DM Mellitus diabetes ESC European Society of Cardiology LVEF Left ventricular ejection fraction AMI Acute myocardial infarction HR Hazard ratio HF Heart failure IRR Internal rate of return NT-proBNP N-terminal pro-B-type natriuretic peptide NYHA New York Association Class OR Odds ratio Declarations Competing interests The authors declare no competing interests. Funding This work was supported in part by grants from CIBER CV (Madrid, Spain) [grant number 16/11/00420]; FEDER (Madrid, Spain), Instituto Carlos III (Madrid, Spain). The authors have no other funding, financial relationships, or conflicts of interest to disclose regarding this work. Author Contribution These authors contributed equally: T.B, G.Z.C.J and J.N conceived the study and designed the experiments. C.J, C.M, E.B, F.C, J.C contribute to data collection. A.P and C.J design the database and statistical analysis. T.B and G.Z contribute equally to the redaction of the manuscript supervised by J.N, A.M and M.L. Data Availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail. 2020;22(8):1342–56. Goodlin SJ, Gottlieb SH. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-4574185\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":321902460,\"identity\":\"37e130a2-20a0-4079-9df0-4ea8cd1eae44\",\"order_by\":0,\"name\":\"Teresa Benito\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Teresa\",\"middleName\":\"\",\"lastName\":\"Benito\",\"suffix\":\"\"},{\"id\":321902462,\"identity\":\"25cc3aa4-447f-4f3a-9e7f-b553418d8635\",\"order_by\":1,\"name\":\"Georgiana Zaharia\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Georgiana\",\"middleName\":\"\",\"lastName\":\"Zaharia\",\"suffix\":\"\"},{\"id\":321902463,\"identity\":\"b8ce6cb7-0c64-4427-9142-91be961f42fe\",\"order_by\":2,\"name\":\"Adora Pérez\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Adora\",\"middleName\":\"\",\"lastName\":\"Pérez\",\"suffix\":\"\"},{\"id\":321902465,\"identity\":\"fed49748-36e1-41a0-b8d4-b164ac6de555\",\"order_by\":3,\"name\":\"Cristina Jaramillo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Cristina\",\"middleName\":\"\",\"lastName\":\"Jaramillo\",\"suffix\":\"\"},{\"id\":321902467,\"identity\":\"83199327-a650-4e66-84dd-5adb179fcb16\",\"order_by\":4,\"name\":\"Miguel Lorenzo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Miguel\",\"middleName\":\"\",\"lastName\":\"Lorenzo\",\"suffix\":\"\"},{\"id\":321902470,\"identity\":\"f737f890-6ace-4517-b1f1-8fba890ec5ed\",\"order_by\":5,\"name\":\"Anna Mollar\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Anna\",\"middleName\":\"\",\"lastName\":\"Mollar\",\"suffix\":\"\"},{\"id\":321902471,\"identity\":\"f2390723-9de6-4591-a3dd-022dccd7f589\",\"order_by\":6,\"name\":\"Carolina Martínez\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Carolina\",\"middleName\":\"\",\"lastName\":\"Martínez\",\"suffix\":\"\"},{\"id\":321902472,\"identity\":\"f64c04c9-5660-4513-ac81-d6536a107af2\",\"order_by\":7,\"name\":\"Evelin Bejarano\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Evelin\",\"middleName\":\"\",\"lastName\":\"Bejarano\",\"suffix\":\"\"},{\"id\":321902473,\"identity\":\"9516f648-447b-4d99-8e0e-79207f15b8a4\",\"order_by\":8,\"name\":\"Francisco Cebrián\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Francisco\",\"middleName\":\"\",\"lastName\":\"Cebrián\",\"suffix\":\"\"},{\"id\":321902474,\"identity\":\"fd4aaeef-6da6-42a1-948d-4899cc5ab018\",\"order_by\":9,\"name\":\"Jose Civera\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jose\",\"middleName\":\"\",\"lastName\":\"Civera\",\"suffix\":\"\"},{\"id\":321902475,\"identity\":\"f636ba0c-4449-4eb9-bafa-88952f578c08\",\"order_by\":10,\"name\":\"Julio Núñez\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYFAC5gYwxQ8iEgqI0sII0SIJohIMSNFicABMEqHB4EZi22PeHTb2xudXJ354YMAgzy92gKCWdmPeM2nMZjfebpYAOsxw5uwEwrZI87YdZjO7cXYDSEuCwW3itPznMZ5xdvMPUrQckDDg791GnC2SZx62Sc5tSzaQuMG7zSLBQIKwX/iOJx+TeNtmZ8/ff3bzzR8VNvL80gS0KByAsSTAKiXwKwcB+QYYi/8AblWjYBSMglEwsgEAZJ5ECTIBdc0AAAAASUVORK5CYII=\",\"orcid\":\"\",\"institution\":\"Hospital Clínico Universitario de Valencia, University of Valencia, INCLIVA\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Julio\",\"middleName\":\"\",\"lastName\":\"Núñez\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-06-13 07:11:51\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-4574185/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-4574185/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1038/s41598-024-72847-5\",\"type\":\"published\",\"date\":\"2024-09-27T15:57:50+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":60024174,\"identity\":\"f184c2c1-69f2-47f7-b3f0-3cb1d1aa032f\",\"added_by\":\"auto\",\"created_at\":\"2024-07-10 16:52:06\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":132494,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eESTE II scale\\u003csup\\u003e7\\u003c/sup\\u003e.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4574185/v1/4c5b908b85f24a980896ffe1.jpg\"},{\"id\":60024172,\"identity\":\"f724cb2f-2c41-4a78-8c76-383124367b6a\",\"added_by\":\"auto\",\"created_at\":\"2024-07-10 16:52:04\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":39659,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eComparison of the continuous score of unwanted loneliness by \\u003cstrong\\u003e2a\\u003c/strong\\u003e. sex, \\u003cstrong\\u003e2b\\u003c/strong\\u003e. widowhood,\\u003cstrong\\u003e 2c\\u003c/strong\\u003e. patients with a previous history of AMI.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4574185/v1/8bf20605e69671a91c73f146.png\"},{\"id\":60024171,\"identity\":\"c98dc804-4aa7-4d8d-98ac-07785a2a8006\",\"added_by\":\"auto\",\"created_at\":\"2024-07-10 16:52:04\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":39149,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eKaplan-Meier failure estimate for the incidence of unwanted loneliness over time. The curve shows that those people who are alone have a greater cumulative probability of experiencing unwanted loneliness over time compared to those who are not alone.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4574185/v1/7270f8e65706197e1606efd0.png\"},{\"id\":65627310,\"identity\":\"a6877f96-76c7-4c98-8d87-cf2b01ff8206\",\"added_by\":\"auto\",\"created_at\":\"2024-09-30 16:14:37\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":803184,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4574185/v1/eaddb1b2-2e33-43f0-ac26-3c351def1182.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Unwanted loneliness in heart failure: risk factors and association with prognosis\",\"fulltext\":[{\"header\":\"INTRODUCTION\",\"content\":\"\\u003cp\\u003eHeart failure (HF) is a clinical syndrome with a high and increasing prevalence\\u003csup\\u003e1\\u003c/sup\\u003e. In addition to its high morbidity and mortality, recent studies in North American and Central European populations suggest that, in chronic pathologies such as HF, unwanted loneliness is common\\u003csup\\u003e2,3\\u003c/sup\\u003e. However, the factors associated are not well defined, particularly in our environment. Furthermore, the evidence on its clinical repercussions is limited and, in many cases, heterogeneous\\u003csup\\u003e4,5\\u003c/sup\\u003e. Biological, psychological and social factors could underline behind the deleterious consequences of unwanted loneliness on health. In this manner, we speculate that unwanted loneliness could be associated with a higher risk of adverse clinical events. In the present study, we sought to evaluate the factors associated with the presence of unwanted loneliness, and the association of this presence with the risk of presenting adverse clinical episodes during follow-up in a population with chronic HF in our environment.\\u003c/p\\u003e\"},{\"header\":\"METHODS\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy population and procedures\\u003c/h2\\u003e \\u003cp\\u003eWe conducted a single-center, cross-sectional, prospective observational study including an unselected cohort of patients meeting the HF criteria, according to the European Society of Cardiology Guidelines 2021\\u003csup\\u003e6\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003e The study sample consisted of consecutive patients who attended the Heart Failure Unit of the Cardiology Service of the Hospital Cl\\u0026iacute;nico Universitario of Valencia from May 2022 to July 2022 and agreed to participate. Patients were included regardless of left ventricular ejection fraction (LVEF).\\u003c/p\\u003e \\u003cp\\u003eDuring the baseline visit, we collected demographic data (age, sex), clinical data (weight, edema, jugular venous distention, body mass index, and medical history), vital signs (heart rate, systolic and diastolic blood pressure, oxygen saturation), electrocardiogram, and laboratory parameters (NT-proBNP, CA125, urea, creatinine, uric acid, sodium, potassium, and hemoglobin), echocardiographic values (LVEF), and pharmacological treatment. We obtained demographic, clinical, and analytical parameters on the same day as the loneliness questionnaire results. Echocardiographic parameters were extracted from the patient's medical history, using values closest to the baseline visit.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAssessment of unwanted loneliness\\u003c/h2\\u003e \\u003cp\\u003eWe evaluated unwanted loneliness using the validated ESTE II questionnaire\\u003csup\\u003e7\\u003c/sup\\u003e. This questionnaire evaluates unwanted loneliness considering three factors including the perception of social support, the use of new technologies and the subjective social participation index. The questions that underlie each of the questionnaire factors are reflected in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. The total score ranges between 0 and 30, with higher scores indicating greater loneliness. Based on the score obtained in each of the responses, we classified patients into three established levels of unwanted loneliness\\u003csup\\u003e7\\u003c/sup\\u003e: low (0\\u0026ndash;10), medium (\\u003cspan additionalcitationids=\\\"CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19\\\" citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e) and high (21\\u0026ndash;30).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eClinical endpoints\\u003c/h2\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eFollow-up and Endpoints\\u003c/h2\\u003e \\u003cp\\u003eWe recorded all-cause admissions and all-cause urgent visits during the follow-up. The primary endpoint was the incidence of all-cause hospitalizations and the composite of all-cause admissions or visits to the emergency department during follow-up. Similarly, we evaluated the time to the first event of the combined death/admission for all causes. We defined admission as any unscheduled hospital stay\\u0026thinsp;\\u0026gt;\\u0026thinsp;24 hours and emergency visits as unplanned visits\\u0026thinsp;\\u0026le;\\u0026thinsp;24 hours. The personnel in charge of endpoint adjudications were blinded to the grade of unwanted loneliness survey.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e \\u003cp\\u003eWe expressed continuous variables as mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;standard deviation or median (25% percentile \\u0026minus;\\u0026thinsp;75% percentile), as appropriate. We presented categorical variables as percentages. We evaluated differences between baseline variables and unwanted loneliness using the chi-square test for categorical variables and T-test or Kruskal-Wallis test for continuous variables. We used logistic and multiple linear regressions to evaluate risk factors associated with loneliness (ESTE score\\u0026thinsp;\\u0026gt;\\u0026thinsp;10) and the continuous ESTE score, respectively. We present results as odds ratios (OR) and β coefficients, respectively. We analyzed the contribution of covariates to the final multivariate logistic regression model's variability using the coefficient of determination (R2). For recurrent events (all events during follow-up: all-cause hospitalizations, emergency visits, or death), we used negative binomial regression and presented risk differences as incidence rate ratios (IRR). We used multivariate Cox regression to examine the association between loneliness and time to the first adverse event, presenting results as hazard ratios (HR).\\u003c/p\\u003e \\u003cp\\u003eWe selected covariates in multivariate models based on biological plausibility, regardless of p-value. The final prognostic multivariate models included a set of 10 covariates: age (years), female (yes/no), widowed (yes/no), New York Heart Association (NYHA) functional class (\\u0026ge;\\u0026thinsp;3), LVEF (% ), previous history of Acute Myocardial Infarction (AMI) (yes/no), type 2 DM (yes/no), previous history of stroke (yes/no), cancer (yes/no) and NT-proBNP (pg/ ml).\\u003c/p\\u003e \\u003cp\\u003eWe conducted all analyses with: STATA 16.1 [Stata Statistical Software, Release 16 (2019); StataCorp LP, College Station, TX, USA].\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eEthics statement\\u003c/h2\\u003e \\u003cp\\u003e The Ethics Committee of the Hospital Cl\\u0026iacute;nico Universitario of Valencia approved the study in accordance with the principles of the Declaration of Helsinki. All patients gave their informed consent.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"RESULTS\",\"content\":\"\\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eBasal characteristics\\u003c/h2\\u003e \\u003cp\\u003eThe mean age of the sample was 75.8\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;9.4 years, 111 (37.2%) were women, 53 (17.8%) were widows, 154 (51.7%) showed heart failure with preserved LVEF, and 260 (87.2%) were in stable NYHA II functional class. The median value (p25% - p75%) of the ESTE II score was 9.0 (6.0\\u0026ndash;12.0) and 36.9% showed unwanted loneliness\\u0026thinsp;\\u0026gt;\\u0026thinsp;10. Subjects with unwanted loneliness were older [79.0 (72.0\\u0026ndash;86.0) vs. 75.0 (67.0\\u0026ndash;81.0), p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001]; more frequently women [63 (54.8%) vs. 52 (45.2%), p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001]; and more were in a state of widowhood [38 (33.0%) vs. 15 (8.2%), p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001]. Regarding clinical variables, unwanted loneliness was more frequent in patients with NYHA III/IV functional class [15 (13.1% vs. 14 (7.7%), p\\u0026thinsp;=\\u0026thinsp;0.032]), also showing lower weight [73 .1 (63.4\\u0026ndash;85.3) vs. 76.8 (70.7\\u0026ndash;88.9), p\\u0026thinsp;=\\u0026thinsp;0.011]; worse estimated glomerular filtration rate [49.6 (37.1\\u0026ndash;61.8) vs. 55.9 (38.9\\u0026ndash;75.2), p\\u0026thinsp;=\\u0026thinsp;0.017]; and less history of AMI [10 (8.7%) vs 41 (22.4%), p\\u0026thinsp;=\\u0026thinsp;0.002]. The baseline characteristics of the population according to the presence of unwanted loneliness are shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eBasaline characteristics.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVariables\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eAlone\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNot alone\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eAll\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003ep-value\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003en\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e115\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e183\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e298\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c5\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eDemographics and previous medical history\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge, years\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e79.0 (72.0-\\u003c/p\\u003e \\u003cp\\u003e86.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e75.0 (67.0-\\u003c/p\\u003e \\u003cp\\u003e81.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e76.5 (69.0-\\u003c/p\\u003e \\u003cp\\u003e84.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLoneliness, score\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e13.0 (12.0\\u0026ndash;16.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7.0 (5.0\\u0026ndash;9.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e9.0 (6.0\\u0026ndash;12.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFemale, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e63 (54.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e48 (26.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e111 (37.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eWidow, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e38 (33.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e15 (8.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e53 (17.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBMI, Kg/m^2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e28.3 (24.8\\u0026ndash;32.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e27.9 (25.0-31.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e28.1 (25.0-31.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.704\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHypertension, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e83 (72.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e132 (72.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e215 (72.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.994\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMellitus Diabetes, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e53 (46.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e80 (43.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e133 (44.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.428\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDyslipidemia, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e60 (52.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e96(52.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e156 (52,3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.962\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePrevious history of AMI, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10 (8.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e41(22.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e51 (17.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.002\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePrevious history of stroke, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3 (2.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e13 (7.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e16 (5.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.094\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHistory of cancer, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e9 (7.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9 (4.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e18 (6.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.305\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNYHA III//IV, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e15 (13.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e14 (7.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e29 (9.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.032\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c5\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eVital Signs and ECG\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHeart rate, bpm.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e71.0 (6.0-\\u003c/p\\u003e \\u003cp\\u003e78.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e71.0 (61.0-\\u003c/p\\u003e \\u003cp\\u003e80.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e71.0 (62.0-\\u003c/p\\u003e \\u003cp\\u003e74.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.538\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSystolic blood pressure, mmHg\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e125.0\\u003c/p\\u003e \\u003cp\\u003e(112.0-140.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e125.0 (111.0-\\u003c/p\\u003e \\u003cp\\u003e139.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e125.0 (112.0-\\u003c/p\\u003e \\u003cp\\u003e139.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.781\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDiastolic blood pressure,\\u003c/p\\u003e \\u003cp\\u003emmHg\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e66.0 (60.0\\u0026ndash;75.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e68.0 (61.0\\u0026ndash;74.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e67.0 (60.0\\u0026ndash;74.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.666\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAtrial fibrillation, (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e54 (47.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e82 (44.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e136 (45.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.717\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c5\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eLaboratory values\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHemoglobin, g/dL\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e13.5 (12.2\\u0026ndash;14.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e14.0 (12.5\\u0026ndash;15.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13.8 (12.4\\u0026ndash;15.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.062\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGFR CDK-EPI, mL/min/1,73m2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e49.6 (37.1\\u0026ndash;61.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e55.9 (38.9\\u0026ndash;75.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e51.8 (38.2\\u0026ndash;72.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.017\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSodium, mEq/L\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e140.0 (138.0-141.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e140.0 (138.0-142.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e140.0 (138.0-142.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.198\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNT-proBNP, pg/mL\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1275.0 (545.0-\\u003c/p\\u003e \\u003cp\\u003e2167.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e947.0 (372.0-\\u003c/p\\u003e \\u003cp\\u003e2485.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1073.5 (404.0-\\u003c/p\\u003e \\u003cp\\u003e2225.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.266\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCA125, U/mL\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e16.0 (10.0\\u0026ndash;22.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e13.0 (9.0\\u0026ndash;19.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13.0 (9.0\\u0026ndash;21.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.569\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c5\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eEchocardiography\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLVEF, %\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e53.0 (41.0-\\u003c/p\\u003e \\u003cp\\u003e60.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e48.0 (38.0-\\u003c/p\\u003e \\u003cp\\u003e58.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e50.0 (39.0-\\u003c/p\\u003e \\u003cp\\u003e59.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.071\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c5\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eMedical treatment\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDiuretics, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e101 (87.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e152 (83.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e253 (84.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.263\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eARNI, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e40 (34.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e72 (39.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e112 (37.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.429\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eARB, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e21 (18.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e32 (17.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e53 (17.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.865\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMRA, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e59 (51.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e80 (43.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e139 (46.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.201\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eβ-blockers, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e82 (71.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e140 (76.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e222 (74.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.316\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eARB: angiotensin II receptor blockers; MRA: mineralocorticoid receptor antagonists; CA125: carbohydrate antigen 125; LVEF: left ventricular ejection fraction; BMI: body mass index; ARNI: angiotensin receptor\\u0026ndash;neprilysin inhibitor; bpm: beats per minute; GFR: glomerular filtration rate; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: \\u003cem\\u003eNew York Heart Association\\u003c/em\\u003e.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eRisk factors associated with loneliness\\u003c/h2\\u003e \\u003cp\\u003eThe independent factors associated with the presence of unwanted loneliness were female sex (OR\\u0026thinsp;=\\u0026thinsp;2.09; 95% CI: 1.11 to 3.98, p\\u0026thinsp;=\\u0026thinsp;0.023) and widowhood (OR\\u0026thinsp;=\\u0026thinsp;3.25; 95% CI: %:1.51 to 7.01, p\\u0026thinsp;=\\u0026thinsp;0.003). On the contrary, a history of previous AMI showed as a protective factor (OR\\u0026thinsp;=\\u0026thinsp;0.39; 95% CI:0.17 to 0.89, p\\u0026thinsp;=\\u0026thinsp;0.025). Variables related to the severity of HF such as NYHA functional class (p\\u0026thinsp;=\\u0026thinsp;0.293), comorbidities [DM (p\\u0026thinsp;=\\u0026thinsp;0.095) and stroke (p\\u0026thinsp;=\\u0026thinsp;0.073)], LVEF (p\\u0026thinsp;=\\u0026thinsp;0.488), NT-proBNP (p\\u0026thinsp;=\\u0026thinsp;0.248) and glomerular filtration rate (p\\u0026thinsp;=\\u0026thinsp;0.398), were not associated with the risk of loneliness.\\u003c/p\\u003e \\u003cp\\u003eIn the analysis of ESTE II score as a continuous variable, multiple linear regression showed that both women (β coefficient\\u0026thinsp;=\\u0026thinsp;2.25; 95% CI: 0.88 to 3.62, p\\u0026thinsp;=\\u0026thinsp;0.001) and widowhood (β coefficient\\u0026thinsp;=\\u0026thinsp;1.96; 95% CI:0.33 to 3.58, p\\u0026thinsp;=\\u0026thinsp;0.018) were significantly and positively associated with the ESTE II score (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003ea and \\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eb, respectively). On the contrary, the previous history of AMI was once again a protective factor (β-coefficient=-1.55; 95% CI: -3.03 to -0.78, p\\u0026thinsp;=\\u0026thinsp;0.039) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003ec). Age showed a positively and numerically association with the ESTE score; however, this association did not reach statistical significance (β-coefficient\\u0026thinsp;=\\u0026thinsp;0.05; 95% CI: -0.01 to 0.12, p\\u0026thinsp;=\\u0026thinsp;0.115).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eUnwanted loneliness: relation with recurring admissions and visits to the emergency room\\u003c/h2\\u003e \\u003cp\\u003eDuring a median (p25%-p75%) follow-up of 362 days (323\\u0026ndash;384), 22 (7.4%) deaths, we recorded 22 deaths (7.4%), 102 hospitalizations in 84 patients (28.3%), and 391 all-cause hospitalizations or emergency visits in 168 patients (56.4%). HF caused a total of 34 hospitalizations in 27 patients. The rate of admission for all causes was significantly higher in those with unwanted loneliness (6.7 vs. 4.4 per 10 person-years, p\\u0026thinsp;=\\u0026thinsp;0.031). These risk differences were maintained after multivariate adjustment. Thus, unwanted loneliness doubled the risk of admission for all causes (IRR\\u0026thinsp;=\\u0026thinsp;2.05; 95% CI: 1.24\\u0026ndash;3.40, p\\u0026thinsp;=\\u0026thinsp;0.005). When we evaluated the association between self-perceived loneliness and the adverse episode composed of all admissions or visits to the emergency room, it corroborated once again that those subjects with loneliness presented higher rates (16.3 vs. 12.9 per 10 person-year, p\\u0026thinsp;=\\u0026thinsp;0.029). This increased risk was also maintained after multivariate analysis (IRR\\u0026thinsp;=\\u0026thinsp;1.42; 95% CI: 1.02\\u0026ndash;1.96, p\\u0026thinsp;=\\u0026thinsp;0.037).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eUnwanted loneliness and morbimortality risk\\u003c/h2\\u003e \\u003cp\\u003eDuring follow-up, 93 patients (31.3%) presented the combined episode of death or all-cause admissions. The risk of this combined episode was higher in those with self-perceived loneliness (5.1 vs 3.3 per 10-person-year, p\\u0026thinsp;=\\u0026thinsp;0.021), with differences that increased progressively throughout follow-up (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e). Multivariate Cox regression confirmed that unwanted loneliness increased the risk of dying or being admitted for any cause (HR\\u0026thinsp;=\\u0026thinsp;1.83; 95% CI: 1.18 to 2.84, p\\u0026thinsp;=\\u0026thinsp;0.007).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"DISCUSSION\",\"content\":\"\\u003cp\\u003eIn this study, we found that in patients with HF, female sex and widowhood are factors associated with unwanted loneliness, while a history of AMI appears as a protective factor. It also confirms that self-perceived loneliness associates with greater risk of poor prognosis during follow-up. From Sullivan's\\u003csup\\u003e8\\u003c/sup\\u003e definition to the present, loneliness has gained relevance as a risk factor that contributes negatively to mental health, physical health, health behavior, and the risk of death \\u003csup\\u003e5,9,10\\u003c/sup\\u003e. Simultaneously, concepts related to loneliness have been narrowed down (including loneliness and social isolation) and multiple scales have been developed for research\\u003csup\\u003e11\\u003c/sup\\u003e. Although not universally adopted, the WHO defines \\u0026ldquo;loneliness\\u0026rdquo; as a painful subjective feeling \\u0026ndash; \\u0026ldquo;social pain\\u0026rdquo; \\u0026ndash; resulting from a discrepancy between desired and actual social connections, and \\u0026ldquo;social isolation\\u0026rdquo; as the state goal of having a small network of family and non-family relationships and, therefore, few or infrequent interactions with others\\u003csup\\u003e5\\u003c/sup\\u003e. The ESTE II Social Loneliness Scale was developed and validated at the University of Granada in our country in 2009 and delves into social loneliness understood as the perception and experience that a subject has in relation to their membership in a social network\\u003csup\\u003e7\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec15\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eLoneliness in HF: previous evidence\\u003c/h2\\u003e \\u003cp\\u003eThe association between loneliness-social isolation and health deterioration is bidirectional\\u003csup\\u003e12,13\\u003c/sup\\u003e. Most studies linking unwanted loneliness and HF have focused on investigating the role of loneliness and/or social isolation as a risk factor for developing HF. There is a consistent association between loneliness and/or social isolation with coronary heart disease\\u003csup\\u003e14\\u0026ndash;16\\u003c/sup\\u003e, however, the evidence for an association between unwanted loneliness and the development of HF is limited and inconclusive, probably due to heterogeneity in the definition of loneliness. A prospective study of a cohort of men between 60 and 79 years selected from General Practice clinics in 24 British cities stated that low social contact increased the risk of HF\\u003csup\\u003e17\\u003c/sup\\u003e. Cen\\u0026eacute; et al. showed that social isolation increased the risk of HF independently of traditional cardiovascular risk factors in a cohort of postmenopausal women without a previous diagnosis of HF from the Women's Health Initiative\\u003csup\\u003e4\\u003c/sup\\u003e. Similarly, in a population cohort extracted from the UK Biobank database, Liang et al. concluded that loneliness and social isolation are independently associated with the development of HF regardless of genetic risk\\u003csup\\u003e18\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eThe scientific literature related to unwanted loneliness and the factors associated with patients already diagnosed with HF is also scarce. In our study, the percentage of loneliness in patients with HF was 36.9%. Previous studies show quite different figures for unwanted loneliness, between 20% and 78%\\u003csup\\u003e19\\u0026ndash;21\\u003c/sup\\u003e. Presence of medium-high grade of loneliness was more homogeneous (20\\u0026ndash;25%) with validated sacles\\u003csup\\u003e19,20\\u003c/sup\\u003e than when loneliness was measured with non-validated scales (78%)\\u003csup\\u003e21\\u003c/sup\\u003e. In Spain, the prevalence of unwanted loneliness in people aged 65 or older is 20%, being slightly higher in women\\u003csup\\u003e22\\u003c/sup\\u003e. The high prevalence in our study could be due to many reasons: a) the type of the scale used; b) older age; c) the chronic nature of HF; d) the size of the sample; and e) the subgroup of the population studied. \\u003csup\\u003e23,24,25\\u003c/sup\\u003e. The present results show that loneliness in patients with HF is associated with female sex (a result that agrees with the rest of the studies in patients with HF)\\u003csup\\u003e19\\u0026ndash;21\\u003c/sup\\u003e and with widowhood. The widowhood has not usually been evaluated in this particular context. However, previous studies suggest that, in patients with HF, being married\\u003csup\\u003e20\\u003c/sup\\u003e or living with someone\\u003csup\\u003e19\\u003c/sup\\u003e is shown to be a protective factor for the development of social isolation or loneliness. In the same sense, living alone was a risk factor for the development of loneliness in multi-pathological patients over 50 years of age in Southeastern Europe\\u003csup\\u003e26\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eWhat stands out in our study is the result that links a history of AMI as a protective factor for the presence of unwanted loneliness in patients with HF. Previous studies have not shown any relationship between a history of ischemic heart disease and loneliness in this patient profile\\u003csup\\u003e19,20\\u003c/sup\\u003e. As mentioned previously, loneliness is a risk factor for the development of ischemic heart disease and has been equated to other traditional cardiovascular risk factors such as obesity and smoking\\u003csup\\u003e10\\u003c/sup\\u003e. It is therefore striking that, in our study, a history of AMI is shown as a protective factor for the development of loneliness. The reasons explaining this association are elusive; however, we speculate that the story of AMI culturally resonates as a serious situation. This is why perhaps the people closest to the patient with previous AMI increase their ties to them, thus decreasing the perception of loneliness. Furthermore, patients with ischemic heart disease appear to be the main beneficiaries of cardiac rehabilitation programs that, at least initially, increase social contact.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec16\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePrognostic implications: the importance of measuring unwanted loneliness in HF\\u003c/h2\\u003e \\u003cp\\u003eThe increase in visits to the emergency room, hospitalization, addition in days of hospitalization, and consumption of other health resources in patients with unwanted loneliness in different clinical scenarios has been demonstrated on several occasions since the original study by Gellers et al. \\u003csup\\u003e10,19,20,22\\u003c/sup\\u003e. Regarding the increase in mortality, a recent meta-analysis\\u003csup\\u003e27\\u003c/sup\\u003e concluded that, in general population, loneliness and social isolation were significantly associated with an increased risk of all-cause death, and that social isolation also increased mortality for all causes in individuals with cardiovascular disease. In this manner, the present results seem to confirm the association between unwanted loneliness and worse clinical outcomes already observed in different clinical contexts.\\u003c/p\\u003e \\u003cp\\u003eThe present work confirms the high prevalence of unwanted loneliness in HF, but also adds novel and relevant information about its clinical consequences. Specifically, this is the first work to show that unwanted loneliness in our country could be associated with a greater risk of adverse clinical events in patients with established HF.\\u003c/p\\u003e \\u003cp\\u003eThe causes that explain the association between unwanted loneliness and poorer clinical outcomes in HF seem to be multifactorial, among which we see: a) greater anxiety and stress due to symptoms, b) unhealthy lifestyle habits, c) lack of therapeutic adherence, and d) biological factors.\\u003c/p\\u003e \\u003cp\\u003eGiven its high prevalence and repercussions, it seems sensible to suggest that the evaluation of unwanted loneliness should be done more routinely in the HF care setting. In this way, the identification of the most vulnerable patients could be followed by a closer clinical approach and possibly implement social/psychological intervention strategies that seek to mitigate or reduce the feeling of loneliness. The contribution of improving loneliness in patients with HF to well-being seems feasible. However, how these can contribute to better care and the achievement of better clinical results deserves to be the subject of prospective studies dedicated to this.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec17\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eLimitations\\u003c/h2\\u003e \\u003cp\\u003eSeveral limitations in this study must be acknowledged. Firstly, this is an observational study in which numerous confounding factors may be operating. Second, this is a study carried out in a single center and there may be a selection bias that makes it difficult to extrapolate results to other settings. Third, this study is not designed to understand the social/cultural/psychological/biological mechanisms behind the present findings. Fourth, the power of the present study does not allow us to evaluate clinical adverse events such as mortality in isolation and specific readmissions due to HF.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"CONCLUSIONS\",\"content\":\"\\u003cp\\u003eIn this contemporary cohort of outpatients with HF, a high prevalence of unwanted loneliness is confirmed, which is more common in women and widows. Its presence is associated with worse clinical outcomes during follow-up.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec19\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eDATA AVAILABILITY\\u003c/h2\\u003e \\u003cp\\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cdiv class=\\\"DefinitionList\\\"\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eCA125\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eCarbohydrate antigen 125\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eDM\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eMellitus diabetes\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eESC\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eEuropean Society of Cardiology\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eLVEF\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eLeft ventricular ejection fraction\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eAMI\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eAcute myocardial infarction\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eHR\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eHazard ratio\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eHF\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eHeart failure\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eIRR\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eInternal rate of return\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eNT-proBNP\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eN-terminal pro-B-type natriuretic peptide\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eNYHA\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eNew York Association Class\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eOR\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eOdds ratio\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003c/div\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e \\u003ch2\\u003eCompeting interests\\u003c/h2\\u003e \\u003cp\\u003eThe authors declare no competing interests.\\u003c/p\\u003e \\u003c/p\\u003e\\u003ch2\\u003eFunding\\u003c/h2\\u003e \\u003cp\\u003eThis work was supported in part by grants from CIBER CV (Madrid, Spain) [grant number 16/11/00420]; FEDER (Madrid, Spain), Instituto Carlos III (Madrid, Spain). The authors have no other funding, financial relationships, or conflicts of interest to disclose regarding this work.\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eThese authors contributed equally: T.B, G.Z.C.J and J.N conceived the study and designed the experiments. C.J, C.M, E.B, F.C, J.C contribute to data collection. A.P and C.J design the database and statistical analysis. T.B and G.Z contribute equally to the redaction of the manuscript supervised by J.N, A.M and M.L.\\u003c/p\\u003e\\u003ch2\\u003eData Availability\\u003c/h2\\u003e\\u003cp\\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eGroenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail. 2020;22(8):1342\\u0026ndash;56.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGoodlin SJ, Gottlieb SH. Social Isolation and Loneliness in Heart Failure: Integrating Social Care Into Cardiac Care. JACC Heart Fail. 2023;11(3):345\\u0026ndash;6.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eOlano-Lizarraga M, Wallstr\\u0026ouml;m S, Mart\\u0026iacute;n-Mart\\u0026iacute;n J, Wolf A. Causes, experiences and consequences of the impact of chronic heart failure on the person\\u0026acute;s social dimension: A scoping review. Health Soc Care Community. 2022;30(4):e842-58.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCen\\u0026eacute; CW, Beckie TM, Sims M, Suglia SF, Aggarwal B, Moise N, et al. Effects of Objective and Perceived Social Isolation on Cardiovascular and Brain Health: A Scientific Statement From the American Heart Association. J Am Heart Assoc. 16 August 2022;11(16):e026493.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWHO: World Health Organization. \\u0026lsquo;Social isolation and loneliness among older people.\\u0026rsquo;. 2010;\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMcDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, B\\u0026ouml;hm M, et al. Gu\\u0026iacute;a ESC 2021 sobre el diagn\\u0026oacute;stico y tratamiento de la insuficiencia card\\u0026iacute;aca aguda y cr\\u0026oacute;nica. Rev Esp Cardiol. 1 de junio de 2022;75(6):523.e1-523.e114.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKant\\u0026uacute;n Mar\\u0026iacute;n MA de J, Moral de la Rubia J, Salazar Gonz\\u0026aacute;lez BC, Rosas Carrasco O. Contraste de un modelo de envejecimiento exitoso derivado del modelo de Roy. Cienc -Sum. 2017;24(2 (Julio-Octubre)):126\\u0026thinsp;\\u0026ndash;\\u0026thinsp;36.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCortina M. Harry Stack Sullivan and Interpersonal Theory: A Flawed Genius. Psychiatry. 2020;83(1):103\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eUmberson D, Montez JK. Social relationships and health: a flashpoint for health policy. J Health Soc Behav. 2010;51 Suppl(Suppl):S54-66.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFreedman A, Nicolle J. Social isolation and loneliness: the new geriatric giants: Approach for primary care. Can Fam Physician Med Fam Can. marzo de 2020;66(3):176\\u0026ndash;82.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eVeazie S, Gilbert J, Winchell K, Paynter R, Guise JM. Addressing Social Isolation To Improve the Health of Older Adults: A Rapid Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2019 [cited 26 December 2023]. (AHRQ Rapid Evidence Product Reports). Disponible en: \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttp://www.ncbi.nlm.nih.gov/books/NBK537909/\\u003c/span\\u003e\\u003cspan address=\\\"http://www.ncbi.nlm.nih.gov/books/NBK537909/\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLuo Y, Hawkley LC, Waite LJ, Cacioppo JT. Loneliness, health, and mortality in old age: a national longitudinal study. Soc Sci Med 1982. marzo de 2012;74(6):907\\u0026ndash;14.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCohen-Mansfield J, Shmotkin D, Goldberg S. Loneliness in old age: longitudinal changes and their determinants in an Israeli sample. Int Psychogeriatr. diciembre de 2009;21(6):1160\\u0026ndash;70.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eValtorta NK, Kanaan M, Gilbody S, Ronzi S, Hanratty B. Loneliness and social isolation as risk factors for coronary heart disease and stroke: systematic review and meta-analysis of longitudinal observational studies. Heart Br Card Soc. 1 de julio de 2016;102(13):1009\\u0026ndash;16.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eValtorta NK, Kanaan M, Gilbody S, Hanratty B. Loneliness, social isolation and risk of cardiovascular disease in the English Longitudinal Study of Ageing. Eur J Prev Cardiol. septiembre de 2018;25(13):1387\\u0026ndash;96.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNaito R, Leong DP, Bangdiwala SI, McKee M, Subramanian SV, Rangarajan S, et al. Impact of social isolation on mortality and morbidity in 20 high-income, middle-income and low-income countries in five continents. BMJ Glob Health. marzo de 2021;6(3):e004124.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCoyte A, Perry R, Papacosta AO, Lennon L, Whincup PH, Wannamethee SG, et al. Social relationships and the risk of incident heart failure: results from a prospective population-based study of older men. Eur Heart J Open. enero de 2022;2(1):oeab045.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLiang YY, Chen Y, Feng H, Liu X, Ai QYH, Xue H, et al. Association of Social Isolation and Loneliness With Incident Heart Failure in a Population-Based Cohort Study. JACC Heart Fail. 1 de marzo de 2023;11(3):334\\u0026ndash;44.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eL\\u0026ouml;fvenmark C, Mattiasson AC, Billing E, Edner M. Perceived loneliness and social support in patients with chronic heart failure. Eur J Cardiovasc Nurs. octubre de 2009;8(4):251\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eManemann SM, Chamberlain AM, Roger VL, Griffin JM, Boyd CM, Cudjoe TKM, et al. Perceived Social Isolation and Outcomes in Patients With Heart Failure. J Am Heart Assoc. 23 de mayo de 2018;7(11):e008069.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePolikandrioti M. Perceived Social Isolation in Heart Failure. J Innov Card Rhythm Manag. 15 de junio de 2022;13(6):5041\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMart\\u0026iacute;n Roncero U, Gonz\\u0026aacute;lez-R\\u0026aacute;bago Y, Mart\\u0026iacute;n Roncero U, Gonz\\u0026aacute;lez-R\\u0026aacute;bago Y. Soledad no deseada, salud y desigualdades sociales a lo largo del ciclo vital. Gac Sanit. octubre de 2021;35(5):432\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eOng AD, Uchino BN, Wethington E. Loneliness and Health in Older Adults: A Mini-Review and Synthesis. Gerontology. 2016;62(4):443\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eYanguas J, Pinazo-Henandis S, Tarazona-Santabalbina FJ. The complexity of loneliness. Acta Bio-Medica Atenei Parm. 7 de junio de 2018;89(2):302\\u0026thinsp;\\u0026ndash;\\u0026thinsp;14.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePetitte T, Mallow J, Barnes E, Petrone A, Barr T, Theeke L. A Systematic Review of Loneliness and Common Chronic Physical Conditions in Adults. Open Psychol J. 2015;8(Suppl 2):113\\u0026ndash;32.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCantarero-Prieto D, Pascual-S\\u0026aacute;ez M, Bl\\u0026aacute;zquez-Fern\\u0026aacute;ndez C. Social isolation and multiple chronic diseases after age 50: A European macro-regional analysis. PloS One. 2018;13(10):e0205062.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eYang M, An Y, Wang M, Zhang X, Zhao Q, Fan X. Relationship Between Physical Symptoms and Loneliness in Patients with Heart Failure: The Serial Mediating Roles of Activities of Daily Living and Social Isolation. J Am Med Dir Assoc. mayo de 2023;24(5):688\\u0026ndash;93.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Unwanted Loneliness, Heart Failure, Widowhood, Women\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-4574185/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-4574185/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eIntroduction and Objectives:\\u003c/strong\\u003eHeart failure (HF) is associated with a high prevalence of unwanted loneliness. This study aimed to assess the risk factors associated with unwanted loneliness and its association with the risk of adverse clinical events in a cohort of patients with HF.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods:\\u003c/strong\\u003e We included 298 patients diagnosed with stable HF. Clinical, biochemical, echocardiographic parameters and loneliness using ESTE II scale were assessed. We analyzed risk factors using multivariate logistic regression. We evaluated the association with the risk of recurrent all-cause admissions using negative binomial regression accounting for the risk of death.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults:\\u003c/strong\\u003e The mean age was 75.8±9.4 years, with 111 (37.2%) being women, 53 (17.8%) widowed, and 154 (51.7%) patients having preserved ejection fraction. The median (p25% - p75%) ESTE II score was 9.0 (6.0 – 12.0), and 36.9% experienced loneliness. Both women (OR=2.09; 95% CI: 1.11 to 3.98, p=0.023) and widowhood (OR=3.25; 95% CI: 1.51 to 7.01, p=0.003) were associated with a higher risk of loneliness. During follow-up, loneliness was significantly associated with increased all-cause hospitalizations (IRR=2.05; 95% CI: 1.24-3.40, p=0.005).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusions:\\u003c/strong\\u003e Women and widowhood emerge as risk factors for unwanted loneliness in HF patients. Unwanted loneliness is associated with higher morbidity during follow-up.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Unwanted loneliness in heart failure: risk factors and association with prognosis\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-07-10 16:51:59\",\"doi\":\"10.21203/rs.3.rs-4574185/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2024-07-16T05:43:47+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2024-07-11T19:44:03+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2024-07-11T04:18:30+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"239828382759377931054777536091514795128\",\"date\":\"2024-07-01T15:45:14+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"124868298315379979586436371345971440104\",\"date\":\"2024-06-30T22:50:32+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2024-06-30T20:20:43+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-06-30T19:59:30+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2024-06-23T12:25:56+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-06-18T02:59:07+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Scientific Reports\",\"date\":\"2024-06-13T07:10:26+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"f24d7f95-a929-4a89-bd79-32852bf76d0c\",\"owner\":[],\"postedDate\":\"July 10th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[{\"id\":34037080,\"name\":\"Health sciences/Cardiology/Cardiovascular biology\"},{\"id\":34037081,\"name\":\"Health sciences/Risk factors\"}],\"tags\":[],\"updatedAt\":\"2024-09-30T16:05:01+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-4574185\",\"link\":\"https://doi.org/10.1038/s41598-024-72847-5\",\"journal\":{\"identity\":\"scientific-reports\",\"isVorOnly\":false,\"title\":\"Scientific Reports\"},\"publishedOn\":\"2024-09-27 15:57:50\",\"publishedOnDateReadable\":\"September 27th, 2024\"},\"versionCreatedAt\":\"2024-07-10 16:51:59\",\"video\":\"\",\"vorDoi\":\"10.1038/s41598-024-72847-5\",\"vorDoiUrl\":\"https://doi.org/10.1038/s41598-024-72847-5\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-4574185\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-4574185\",\"identity\":\"rs-4574185\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}