Journal of Clinical Medicine Article Ischemic Etiology and Prognosis in Men and Women with Acute Heart Failure Lourdes Vicent 1 , Jose Guerra 2,3 , Rafael Vazquez-García 4 , José R. Gonzalez-Juanatey 3,5 , Luis Martínez Dolz 6 , Javier Segovia 3,7 , Domingo Pascual-Figal 8 , Ramón Bover 9 , Fernando Worner 10 , Juan Delgado 1,3 , Francisco Fernández-Avilés 3,11,12 and Manuel Martínez-Sellés 3,11,12,13, * 1 Cardiology Department, Hospital Universitario 12 de Octubre, 28028 Madrid, Spain; mlourdesvicent@gmail.com (L.V.); juan.delgado@salud.madrid.org (J.D.) 2 Cardiology Department, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; JGuerra@santpau.cat 3 CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain; Jose.Ramon.Gonzalez.Juanatey@sergas.es (J.R.G.-J.); jsecu@telefonica.net (J.S.); faviles@secardiologia.es (F.F.-A.) 4 Cardiology Department, Puerta del Mar University Hospital, 11009 Cádiz, Spain; rafael.vazquez.sspa@juntadeandalucia.es 5 Cardiology Department, University Hospital, 15076 Santiago de Compostela, Spain 6 Cardiology Department, University Hospital La Fe (CIBERCV), 46026 Valencia, Spain; luismartinezdolz@gmail.com 7 Cardiology Department, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain 8 Cardiology Department, Hospital Virgen de la Arrixaca, Department of Medicine, University of Murcia, 30120 Murcia, Spain; dpascual@um.es 9 Cardiology Department, Hospital Clínico San Carlos, 28040 Madrid, Spain; ramonboverfreire@gmail.com   10 Servicio de Cardiología, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, 25198 Lleida, Spain; fworner.lleida.ics@gencat.cat Citation: Vicent, L.; Guerra, J.; 11 Cardiology Department, Instituto de Investigación, Hospital General Universitario Gregorio Marañón, Vazquez-García, R.; 28007 Madrid, Spain Gonzalez-Juanatey, J.R.; Dolz, L.M.; 12 Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain Segovia, J.; Pascual-Figal, D.; Bover, 13 Facultad de Medicina, Universidad Europea, 28670 Madrid, Spain R.; Worner, F.; Delgado, J.; et al. * Correspondence: mmselles@secardiologia.es; Tel.: +34-915-8686-87 Ischemic Etiology and Prognosis in Men and Women with Acute Heart Abstract: Coronary heart disease is common in heart failure (HF). Our aim was to determine the Failure. J. Clin. Med. 2021, 10, 1713. impact of ischemic etiology on prognosis among men and women with HF. This study is a prospective https://doi.org/10.3390/jcm10081713 national multicenter registry. The primary endpoint was 12-month mortality. Patients with HF and ischemic heart disease were stratified according to sex. A total of 1830 patients were enrolled of Academic Editor: Ali Ahmed which 756 (41.3%) were women. Ischemic etiology was more common in men (446 (41.6%)) than Received: 21 March 2021 in women (167 (22.2%)). Among patients with ischemic HF, diabetes was more frequent in women Accepted: 13 April 2021 than in men. Ischemic etiology was not associated with higher mortality risk, and this was true for Published: 15 April 2021 women (Hazard Ratio [HR] 1.51, 95% Confidence Interval [CI] 0.98–2.32; p = 0.61) and men (HR 1.14, 95% CI 0.81–1.61; p = 0.46), p-value for interaction: 0.067. Mortality/readmission risk in ischemic Publisher’s Note: MDPI stays neutral HF increased in men with previous readmissions (HR 1.15, 95% CI 1.02–1.29; p = 0.022), chronic with regard to jurisdictional claims in obstructive pulmonary disease (HR1.20, 95% CI 1.02–1.41; p = 0.026) and in women with diabetes published maps and institutional affil- (HR 2.23, 95% CI 1.05–4.47; p = 0.035). Ischemic etiology was not associated with mortality in HF iations. patients. In ischemic HF, the variables associated with a poor prognosis were diabetes in women and previous readmissions and chronic obstructive pulmonary disease in men. Keywords: heart failure; mortality; ischemic heart disease Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Ischemic heart disease is the leading cause of mortality worldwide and is a major cause Attribution (CC BY) license (https:// of premature mortality and disability [1]. Ischemic heart disease is a common condition creativecommons.org/licenses/by/ associated with heart failure (HF) and a powerful predisposing factor [2] of developing 4.0/). J. Clin. Med. 2021, 10, 1713. https://doi.org/10.3390/jcm10081713 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 1713 2 of 11 HF [3,4]. In addition, ischemic etiology has been associated with a poor prognosis in HF patients in some studies [5], but not in others [6]. Differences related to sex have been described in HF patients, including etiology, demographic profile, medical history, and prognosis [7–9]. Compared to men, women have a higher prevalence of hypertension, valvular heart disease, and diabetes but a lower prevalence of ischemic heart disease [7,8,10]. However, the effect of sex on the impact of ischemic heart disease on HF prognosis is controversial [11,12]. A worse prognosis has been described in women with coronary artery disease, with an increased risk of incident HF, cardiogenic shock [12], lower frequency of revascularization, and a lower use of antiplatelet drugs, statins, and beta-blockers [10,13,14]. Moreover, women have been underrepresented in clinical trials of HF and ischemic heart disease [15]. Our objective was to assess the impact of ischemic heart disease on HF prognosis in men and women. We have also compared the characteristics and treatment of women admitted with heart failure with their male counterparts. 2. Methods The present study is a sub-analysis of the Spanish Network for the Study of Heart Failure II registry (REDINSCOR II). The methodology of the study has been previously detailed [16,17]. Briefly, the REDINSCOR II is a prospective, multicenter, nationwide study including adults admitted for acute HF in 20 Cardiology departments from Spanish hospitals, from October 2013 to December 2014. According to the definition of the current clinical practice guidelines, all patients had a diagnosis of acute HF at admission [18]. Patients with HF and ischemic heart disease were stratified according to sex. We considered ischemic etiology in the presence of coronary artery disease of sufficient severity and extension to justify myocardial damage [19,20]. The primary endpoint was mortality at 12 months. We also analyzed the composite of all-cause mortality/hospital readmissions due to HF incidence of sudden cardiac death, mortality due to refractory HF, or heart transplantation at 12 months. Hospital readmissions and mortality at 1 and 6 months were also assessed. This study was accomplished with the Declaration of Helsinki and was approved by the Ethics Committee of the recruiting hospitals (9/12/2013 CEIC: 57/2013; 19/09/2013 CEIC: 13/2013). All patients provided written informed consent. Statistical Analysis Continuous variables are shown as mean (standard deviation) or median (interquar- tile interval) for non-normally distributed variables. Categorical data are presented as frequencies and percentages. Continuous quantitative variables were compared using Student’s t-test and ANOVA for the comparison of means or the Wilcoxon rank-sum in nonparametric data. Categorical variables were analyzed using the χ2 test and the Fischer exact test. Bonferroni’s correction was applied for multiple comparisons. Multivariate analysis included multiple logistic regression techniques and Cox regres- sion modeling for the study endpoints. To determine which variables were entered into the final model, we used a sequential inclusion and exclusion method, with an inclusion p threshold lower than 0.05 and exclusion over 0.1. The final model included age, previous heart failure admissions, diabetes, glomerular filtration rate, HF therapies, rhythm, and anemia at discharge. All analyses were performed with the STATA software (StataCorp, College Station, TX, USA, version 14.0). 3. Results A total of 1830 HF patients were enrolled in the registry; the mean age was 73.3 ± 10.6 years, 756 (41.3%) were women, and 613 (33.5%) had ischemic etiology. Ischemic etiology was signifi- cantly more common in men (446 [41.5%]) compared to women (167 (22.1%)), p < 0.001. Table 1 shows basal demographic characteristics in the studied patients according to sex and etiology. Compared to men, women were significantly older, and we found significant differences in J. Clin. Med. 2021, 10, 1713 3 of 11 the frequency of cardiovascular risk factors. Women with ischemic HF had a more common history of diabetes, while men more often had a history of tobacco and alcohol consumption. In patients with non-ischemic HF, the etiology of HF was valvular heart disease in 411 (33.9%), hypertension in 535 (44.1%), idiopathic/familiar in 199 (16.4%), hypertrophic cardiomyopathy in 53 (4.4%), and infiltrative diseases in 15 (1.2%). Table 1. Baseline characteristics in patients admitted with heart failure (HF) according to etiology and sex. Non- Women, Men, Women, Men, Non- Ischemic Ischemic HF p Ischemic HF Ischemic p Non- Ischemic p HF (n = 613) (n = 1218) (n = 167) HF (n = 446) Ischemic HF (n = 629) HF (n = 589) Age (years) 73.3 ± 10.6 71.9 ± 12.8 <0.001 77.2 ± 10.3 71.9 ± 10.4 <0.001 74.7 ± 11.7 69.4 ± 13.3 0.002 Previous heart failure 415 (67.7) 645 (53.0) <0.001 121 (72.5) 294 (65.9) 0.283 327 (55.5) 318 (50.6) 0.002 diagnosis Years since the diagnosis 3.0 ± 5.3 4.0 ± 5.6 0.019 3.4 ± 4.9 4.2 ± 5.9 0.107 3.3 ± 5.8 2.6 ± 4.8 <0.001 Previous heart failure 290 (47.3) 455 (37.3) 0.003 84 (50.3) 206 (46.2) 0.366 220 (37.4) 235 (37.4) 0.997 admissions Tobacco use <0.001 - Smoker 74 (12.1) 361 (29.7) 5 (3.0) 69 (15.5) <0.001 26 (4.4) 307 (49.1) <0.001 - Former smoker 269 (44.0) 119 (9.8) 17 (10.2) 252 (56.6) <0.001 54 (9.2) 93 (14.9) <0.001 Alcohol consumption 54 (8,8) 139 (11.4) 0.002 1 (0.6) 53 (11.9) <0.001 10 (1.7) 129 (20.5) <0.001 Dyslipidemia 429 (70.0) 583 (47.9) <0.001 109 (65.3) 320 (71.8) 0.192 303 (51.4) 280 (44.6) 0.044 Diabetes mellitus 364 (59.4) 483 (39.7) <0.001 115 (68.9) 249 (55.8) 0.010 244 (41.4) 239 (38.1) 0.463 Hypertension 540 (88.1) 874 (71.8) <0.001 150 (89.8) 390 (87.4) 0.547 444 (75.4) 430 (68.5) 0.025 Obesity 282 (46.0) 609 (50.0) 0.106 78 (46.7) 204 (45.7) 0.831 299 (50.8) 310 (49.3) 0.606 Chronic kidney disease <0.001 - GFR < 30 49 (8.1) 49 (4.1) 15 (9.0) 34 (7.6) 0.332 25 (4.2) 24 (3.8) 0.255 - GFR 30–59 171 (28.2) 231 (19.1) 42 (25.1) 129 (28.9) 0.220 108 (18.3) 123 (19.6) 0.148 Chronic obstructive 102 (16.6) 188 (15.5) 0.475 8 (4.8) 94 (21.1) <0.001 53 (9.0) 135 (21.5) <0.001 pulmonary disease Stroke 67 (10.9) 116 (9.5) 0.646 17 (10.2) 50 (11.2) 0.875 52 (8.8) 64 (10.2) 0.609 Peripheral arterial 104 (8.5) 106 (17.3) <0.001 22 (13.2) 84 (18.8) 0.205 48 (8.2) 56 (8.9) 0.395 disease Previous myocardial 412 (67.2) 72 (5.9) <0.001 117 (70.1) 295 (66.1) 0.132 27 (4.6) 45 (7.7) 0.065 infarction Previous coronary artery 227 (37.2) 55 (4.5) <0.001 revascularization - Percutaneous 83 (13.6) 32 (2.6) 61 (36.5) 166 (37.4) 0.232 24 (4.1) 31 (5.0) 0.929 - Surgical 54 (8.8) 15 (1.2) <0.001 20 (12.0) 63 (14.2) 0.210 15 (2.6) 17 (2.7) 0.875 - Both <0.001 9 (5.4) 45 (10.1) 0.199 7 (1.2) 8 (1.3) 0.935 Atrial fibrillation 201 (32.7) 571 (46.9) <0.001 56 (33.5) 145 (32.5) 0.811 288 (48.9) 283 (45.0) 0.362 Implantable cardioverter 61 (10.0) 66 (5.5) 0.002 4 (2.4) 57 (12.8) <0.001 16 (2.7) 50 (8.0) <0.001 defibrillator Implantable cardioverter defibrillator in patients 42 (15.9) 42 (13.3) 0.382 2 (4.8) 40 (95.2) 0.003 7 (16.7) 35 (83.3) 0.126 with a LVEF < 35% Cardiac resynchronization 24 (3.9) 27 (2.2) 0.130 3 (1.8) 21 (4.7) 0.161 10 (1.7) 17 (2.7) 0.485 therapy Previous treatments: ACEIs 290 (47.3) 398 (32.7) <0.001 77 (46.1) 213 (47.8) 0.517 179 (30.4) 219 (34.9) 0.128 ARBs 153 (24.9) 291 (23.9) 0.373 50 (29.9) 103 (23.1) 0.005 156 (26.5) 135 (21.5) 0.093 Betablockers 430 (70.1) 562 (46.1) 0.001 118 (70.7) 312 (70.1) 0.960 282 (48.0) 281 (44.6) 0.012 Ivabradine 52 (8.5) 35 (2.9) <0.001 9 (5.4) 43 (9.6) 0.212 13 (2.2) 22 (3.5) 0.358 Loop diuretics 391 (63.8) 687 (56.5) 0.004 104 (62.3) 287 (64.4) 0.639 354 (60.1) 333 (53.0) 0.043 Mineralocorticoid 182 (29.7) 255 (20.9) <0.001 38 (22.8) 144 (32.3) 0.004 124 (21.1) 131 (20.8) 0.213 receptor antagonists Digoxin 47 (7.7) 151 (12.4) 0.006 12 (7.2) 35 (7.9) 0.894 85 (14.4) 66 (10.5) 0.101 Oral anticoagulation 213 (34.9) 507 (41.7) 0.011 51 (30.5) 162 (36.5) 0.183 275 (46.7) 232 (37.1) 0.001 Aspirin 343 (56.1) 294 (24.2) <0.001 97 (58.1) 246 (55.4) 0.552 128 (21.7) 166 (26.5) 0.075 Clopidogrel 149 (24.4) 48 (3.9) <0.001 40 (24.0) 109 (24.6) 0.878 23 (3.9) 25 (4.0) 0.483 Ticagrelor 9 (1.5) 0 <0.001 5 (3.0) 4 (0.9) 0.073 1 (0.2) 0 0.485 Prasugrel 17 (2.8) 1 (0.1) <0.001 5 (3.0) 12 (2.7) 0.846 0 1 (0.2) 0.250 Data are shown as mean ± standard deviation for continuous variables, and n (%) for categorical. ACEI: Angiotensin Converting Enzyme Inhibitors; ARB: Angiotensin II Receptor Blockers; GFR: Glomerular Filtration Rate; LVEF: Left Ventricular Ejection Fraction. J. Clin. Med. 2021, 10, 1713 4 of 11 In patients with ischemic etiology, men were carriers of an implantable cardioverter- defibrillator more frequently than women (57 (12.8%) vs. 4 (2.4%), p < 0.001), and this was also the case in patients with non-ischemic HF (50 (8.0%) vs. 16 (2.7%), p < 0.001). Concerning pharmacological treatment, women with ischemic etiology more commonly received angiotensin II receptor blockers and fewer mineralocorticoid receptor antagonists compared to men. Left ventricular ejection fraction was higher in women with ischemic etiology, com- pared to men (47 ± 18% vs. 39 ± 16%) (Table 2). Men, however, had greater ventricular remodeling and dilation and a wider QRS duration. Mortality during hospital admission was comparable in men and women (43 (4.0) vs. 28 (3.7)), but length of hospital stay was shorter in women (9.8 ± 8.5 vs. 12.2 ± 17.4). Women with ischemic HF were older, had greater comorbidity, lower left ventricular ejection fraction, and more common previous HF hospitalizations compared to women with non-ischemic HF. Table 2. Vital signs at admission and in-hospital treatments in patients with heart failure (HF) according to etiology and sex. Non- Women, Men, Women, Men, Non- Ischemic Ischemic HF p Ischemic HF Ischemic p Non- Ischemic p HF (n = 613) (n = 1218) (n = 167) HF (n = 446) Ischemic HF (n = 629) HF (n = 589) Systolic blood pressure 134 ± 29 135 ± 30 0.8772 140 ± 29 132 ± 30 0.007 136 ± 28 133 ± 29 0.635 Diastolic blood pressure 75 ± 18 76 ± 18 0.167 73.8 ± 17.7 75.5 ± 18.1 0.300 75 ± 17 77 ± 13 0.263 Heart rate 86 ± 22 91 ± 28 0.002 85.1 ± 23.5 85.9 ± 22.1 0.690 91 ± 28 90 ± 27 0.756 Left bundle branch block 97 (16.7) 179 (15.3) 0.006 24 (15.1) 73 (17.3) 0.793 77 (13.7) 102 (16.9) 0.314 QRS duration (ms) 119 ± 33 113 ± 33 <0.006 110 ± 29 123 ± 35 <0.001 108 ± 31 118 ± 34 0.012 Left ventricular diastolic 58 ± 11 53 ± 11 <0.001 52 ± 9 60 ± 11 <0.001 49 ± 9.6 57 ± 10 0.076 diameter (mm) Left ventricular ejection fraction (%) during 41 ± 17 48 ± 18 <0.001 47 ± 18 39 ± 16 <0.001 54 ± 16 43 ± 18 0.039 admission Moderate-severe mitral 203 (33.3) 401 (32.9) 0.524 51 (30.5) 152 (34.0) 0.622 189 (32.0) 212 (33.7) 0.393 regurgitation Sodium (mEq/L) 138 ± 5 139 ± 5 0.236 138 ± 5 139 ± 4 0.070 139 ± 4 139 ± 5 0.051 Potassium (mmol/L) 4.4 ± 0.7 4.3 ± 0.7 0.033 4.4 ± 0.8 4.3 ± 0.7 0.261 4.3 ± 0.7 4.3 ± 0.7 0.077 Glomerular filtration 60.2 ± 29.4 67.2 ± 30.3 <0.001 61.8 ± 29.9 55.8 ± 27.4 0.024 64.1 ± 29.4 70.1 ± 31.0 0.188 rate (mL/min) NT-proBNP 947 ± 1295 747 ± 904 0.001 990 ± 1363 929 ± 1267 0.657 670 ± 858 829 ± 944 0.051 Haemoglobin (g/L) 12.2 ± 20.1 12.3 ± 21.1 0.011 11.4 ± 14.9 12.3 ± 21.2 <0.001 11.8 ± 17.8 12.8 ± 22.7 <0.001 Non-invasive <0.001 0.085 0.226 mechanical ventilation 36 (5.9) 62 (5.2) 6 (3.7) 30 (6.8) 25 (4.3) 37 (6.0) Invasive mechanical 6 (1.0) 8 (0.7) 0.075 1 (0.6) 5 (1.1) 0.198 2 (0.3) 6 (1.0) 0.210 ventilation Intraaortic balloon pump 3 (0.5) 2 (0.2) <0.001 1 (0.6) 2 (0.5) 0.276 0 2 (0.3) 0.387 Treatments at hospital discharge: ACEIs 339 (55.3) 579 (47.6) 0.006 90 (53.9) 249 (55.8) 0.634 250 (42.4) 329 (52.4) <0.001 ARBs 101 (16.5) 225 (18.5) 0.324 37 (22.1) 64 (14.4) 0.014 119 (20.2) 106 (16.9) 0.265 Betablockers 479 (80.5) 782 (66.3) <0.001 127 (77.9) 352 (81.5) 0.354 282 (47.8) 281 (44.7) 0.012 Ivabradine 70 (11.4) 64 (5.3) <0.001 13 (7.8) 57 (12.8) 0.124 22 (3.7) 42 (6.7) 0.030 Loop diuretics 512 (83.5) 1001 (82.3) 0.792 143 (85.6) 369 (82.7) 0.495 496 (84.2) 505 (80.4) 0.180 Mineralocorticoid 269 (43.9) 525 (43.1) <0.001 62 (37.1) 207 (46.4) 0.003 192 (33.9) 181 (30.2) <0.001 receptor antagonists Digoxin 56 (9.1) 254 (20.9) <0.001 16 (9.6) 40 (9.0) 0.814 134 (22.8) 120 (19.1) 0.287 Oral anticoagulation 266 (44.7) 696 (58.9) <0.001 66 (40.2) 200 (46.4) 0.176 369 (64.2) 327 (54.1) <0.001 Aspirin 369 (62.0) 302 (25.6) <0.001 101 (61.6) 268 (62.2) 0.495 123 (21.4) 179 (29.6) 0.001 Clopidogrel 174 (29.2) 72 (6.1) <0.001 48 (29.3) 126 (29.2) 0.994 27 (4.7) 45 (7.4) 0.018 Ticagrelor 13 (2.2) 2 (0.2) <0.001 8 (4.9) 5 (1.2) 0.010 0 2 (0.3) 0.035 Prasugrel 9 (1.5) 1 (0.1) <0.001 3 (1.8) 6 (1.4) 0.712 0 1 (0.2) 0.069 J. Clin. Med. 2021, 10, 1713 5 of 11 Table 2. Cont. Non- Women, Men, Women, Men, Non- Ischemic Ischemic HF p Ischemic HF Ischemic p Non- Ischemic p HF (n = 613) (n = 1218) (n = 167) HF (n = 446) Ischemic HF (n = 629) HF (n = 589) Percutaneous coronary artery revascularization 66 (11.0) 35 (2.9) <0.001 17 (10.4) 49 (11.2) 0.651 12 (2.1) 23 (3.7) 0.171 during admission Surgical coronary artery revascularization during 6 (0.5) 12 (2.0) 0.013 1 (0.6) 11 (2.5) 0.172 3 (0.5) 3 (0.5) 0.726 admission Death during hospital 45 (3.7) 26 (4.3) 0.851 8 (4.8) 18 (4.0) 0.202 20 (3.4) 25 (4.0) 0.703 admission Length of hospital stay 11.1 ± 9.5 11.3 ± 16.4 0.837 8.8 ± 5.5 12.0 ± 10.5 0.002 10.1 ± 9.1 12.4 ± 21.0 <0.001 (days) Data are shown as mean ± standard deviation for continuous variables, and n (%) for categorical. ACEI: Angiotensin Converting Enzyme Inhibitors; ARB: Angiotensin II Receptor Blockers; NT-proBNP: N-terminal (NT)-pro hormone BNP. Unadjusted analysis of mortality and hospital readmissions showed similar outcomes during follow-up among men and women with ischemic etiology of HF (Table 3). However, women with non-ischemic etiology tended to present fewer hospital readmissions at 12 months. In adjusted Cox regression analysis, ischemic etiology was not associated with an increased mortality at 12 months in women (HR 1.52, 95% CI 0.97–2.33, p = 0.052) or men (HR 1.28, 95% CI 0.911–1.79, p = 0.155) (Figure 1). Women received a heart transplant less often compared to men in univariate comparisons (5 (0.7%) vs. 31 (2.9%), p = 0.05). After a multivariate analysis adjusting for age and comorbidities, we did not find sex-related differences in heart transplants at 12 months (HR 2.53, 95% CI 0.87–7.39; p = 0.09). The only factor associated with a lower indication of heart transplants was older age (HR 0.92, 95% CI 0.89–0.94; p < 0.001). Table 3. Events during follow-up in patients admitted with heart failure (HF) according to etiology and sex. Women, Men, Women, Men, Ischemic HF Ischemic HF p Non-Ischemic HF Non-Ischemic HF p (n = 167) (n = 446) (n = 589) (n = 629) Hospital readmissions 57 (34.1) 146 (32.7) 0.773 181 (30.7) 159 (25.3) 0.034 due to HF at 12 months All-cause mortality at 42 (25.2) 102 (22.9) 0.593 111 (18.9) 120 (19.1) 0.918 12 months Heart transplant at 1 (0.6) 13 (2.9) 0.050 4 (0.7) 18 (2.9) 0.004 12 months Sudden cardiac death at 4 (2.4) 18 (4.0) 0.331 10 (1.7) 23 (3.7) 0.035 12 months Death due to refractory 19 (11.4) 52 (11.7) 0.923 59 (10.0) 44 (7.0) 0.058 heart failure Death due to non-cardiac 13 (7.8) 24 (5.4) 0.259 25 (4.2) 36 (5.7) 0.293 causes Data are shown as mean ± standard deviation for continuous variables, and n (%) for categorical. Ischemic etiology was not an independent predictor of mortality (HR 1.21, 95% CI 0.96–1.53, p = 0.11) (Table 4), and this was true for women (HR 1.51, 95% CI 0.98–2.32; p = 0.61) and men (HR 1.14, 95% CI 0.81–1.61; p = 0.46), interaction p-value: 0.067. Ischemic etiology was also not associated with the combined endpoint of mortality/readmissions. In patients with ischemic HF, diabetes was associated with an increased risk of mortal- ity/readmissions in women and previous HF admissions and chronic obstructive pul- monary disease in men. J. Clin. Med. 2021, 10, 1713 6 of 11 Figure 1. Show Kaplan–Meier survival curves of mortality at 12 months according to HF etiology, in men and women. Table 4. Independent predictors of mortality, and mortality/readmissions at 12 months in patients admitted with heart failure (HF) according to etiology and sex. Women, Ischemic HF 12-Month Mortality HR (95% CI) p - ACEIs/ARBs 0.58 (0.24–0.97) 0.041 12-Month Mortality/Readmissions HR (95% CI) p - Diabetes mellitus 2.23 (1.05–4.47) 0.035 Men, Ischemic HF 12-Month Mortality HR (95% CI) p - Age 1.03 (1.01–1.05) 0.010 - ACEIs/ARBs 0.58 (0.33–0.79) 0.002 12-Month Mortality/Readmissions HR (95% CI) p - Previous HF admissions 1.15 (1.02–1.29) 0.022 - Chronic obstructive pulmonary disease 1.20 (1.02–1.41) 0.026 Women, Non-Ischemic HF 12-Month Mortality HR (95% CI) p - Age 1.04 (1.14–1.06) 0.002 - Diabetes mellitus 1.34 (1.13–1.58) 0.001 - Chronic kidney disease 1.28 (1.07–1.52) 0.008 - ACEIs/ARBs 0.46 (0.31–0.69) <0.001 J. Clin. Med. 2021, 10, 1713 7 of 11 Table 4. Cont. Women, Non-Ischemic HF 12-Month Mortality/Readmissions HR (95% CI) p - Previous HF admissions 1.25 (1.14–1.38) <0.001 Men, Non-Ischemic HF 12-Month Mortality HR (95% CI) p - Age 1.05 (1.03–1.67) <0.001 - Previous HF admissions 1.88 (1.03–1.67) 0.004 - Chronic kidney disease 1.22 (1.08–1.39) 0.002 - ACEIs/ARBs 0.61 (0.40–0.91) 0.015 12-Month Mortality/Readmissions HR (95% CI) p - Age 1.02 (1.01–1.03) 0.021 - Previous HF admissions 1.28 (1.17–1.39) <0.001 - ACEIs/ARBs 0.69 (0.50–0.97) 0.033 ACEI: Angiotensin Converting Enzyme Inhibitors; ARB: Angiotensin II Receptor Blockers; CI: Confidence Interval; HF: Heart Failure; HR: Hazard Ratio. 4. Discussion We have found that, among patients admitted with HF, ischemic etiology is present in a fifth of women and about 40% of men. Ischemic etiology was not associated with an increased risk of adverse events. 4.1. Comorbidities and Cardiovascular Risk Factors Women are underrepresented in clinical trials, and patients from clinical trials are highly selected. Our sample is more representative of real-world patients. Previous studies that have analyzed HF’s presentation in women have shown frequent advanced age and comorbidity [21–24]. In contrast to men, the most common form of HF in women is that with preserved left ventricular function [22]. Our results were consistent with previous experiences, as women had higher left ventricular ejection fraction and older age [8,21,25]. Regarding comorbidity and cardiovascular risk factors, women with ischemic etiology frequently had diabetes (69%), but the rate of hypertension was comparable to men (Supplementary Materials). It is possible that high blood pressure plays a less prominent role in the development of ischemic heart disease in women, which would be more related to other cardiovascular risk factors, such as diabetes [23,26]. HF risk is higher in women with diabetes than in men with diabetes [23,26–28]. Analyzing the characteristics of women with ischemic etiology, we have observed that the clinical profile of these patients is more similar to men with ischemic HF than to women with HF of non-ischemic etiology, suggesting that several differences associated with sex might be, in fact, related to ischemic etiology. 4.2. Heart Failure Therapies The use of a implantable cardioverter-defibrillator was higher in men than in women. This might be related, in part, to the fact that men more frequently had a left ventricular J. Clin. Med. 2021, 10, 1713 8 of 11 ejection fraction <35% [18,25]. However, it has also previously been stated that women with HF and a reduced left ventricular ejection fraction are less likely to be referred for cardioverter-defibrillator implantation [29]. In fact, in the specific group of patients with ischemic etiology and reduced left ventricular ejection fraction, the proportion of women with a defibrillator was also lower than men. In our study, the incidence of sudden cardiac death during follow-up was similar between men and women with ischemic HF. Traditionally, women with HF have been under-treated compared to men. This difference has been attributed to women’s more unfavorable clinical profile, with older age and common comorbidities [30]. However, in the subgroup of women with ischemic etiology, we only found significant differences in the prescription of mineralocorticoid receptor antagonists. The lower prescription of these drugs in the cohort of our study may also be explained by the lack of indication due to the higher left ventricular ejection fraction in women [25]. 4.3. Mortality and Hospital Readmissions during Follow-Up We did not find significant sex differences in hospital mortality and mortality/readmissions during follow-up among patients with ischemic HF. In some previous studies, women have shown better-adjusted survival rates than in men [16,29,31–33], a finding which is more marked in patients with non-ischemic HF [23,34,35]. In our registry patients, the survival advantage traditionally attributed to women with non-ischemic heart failure may have been attenuated by a more advanced disease, with more years since the diagnosis. With regard to hospitalization for heart failure, previous experiences have described that the male sex is associated with a higher probability of readmission [36,37] and the combined endpoint of mortality/readmissions [36]. The attenuation of these sex-related differences in prognosis could be explained by HF’s etiology and the negative impact of coronary heart disease in women. Indeed, women who present with an acute myocardial infarction have an increased risk of developing heart failure during admission and follow- up, compared to men [11,12]. Mental/psychological stress was not assessed in this study. Future studies should analyze the impact of psychosocial dimension on the prognosis of patients with HF according to etiology, and sex differences. Other variables associated with worse outcomes were comorbidities, especially di- abetes mellitus or chronic obstructive pulmonary disease in women, and previous hos- pitalizations in men with ischemic etiology. Treatment with ACEIs/ARBs was a factor associated with a lower risk of death and readmissions, regardless of sex and the etiology of heart failure. Women tend to receive heart transplants less often than men [38]. In the univariate analysis of our study, heart transplants were performed less frequently in women. However, after multivariate adjustment, there were no differences between men and women with ischemic or non-ischemic etiology of HF. Advanced age was the only factor associated with a lower probability of receiving a heart transplant, and therefore, after statistical adjustment, the indication for transplant was similar in both sexes. Our study has some limitations. The follow-up phase was 12 months, and a longer follow-up period may have shown significant differences in outcomes according to HF etiology and sex. The dosage of disease-modifying drugs was not recorded, and we do not have information about patients who presented appropriate defibrillator shocks during follow-up. 5. Conclusions Compared to patients with non-ischemic etiology, patients with ischemic HF have more comorbidities. Ischemic etiology was not associated with mortality in HF patients. In ischemic HF, the variables associated with a poor prognosis were diabetes in women, and previous readmissions and chronic obstructive pulmonary disease in men. Additional J. Clin. Med. 2021, 10, 1713 9 of 11 studies are required to determine the specific impact of other etiologies on the prognosis of HF. Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/jcm10081713/s1, Table S1: Basal demographic and clinical characteristics of patients with HF according to sex and etiology. Author Contributions: Conceptualization: M.M.-S. and L.V.; Methodology, M.M.-S. and L.V.; Soft- ware, M.M.-S. and L.V.; Validation, J.G., L.M.D., R.V.-G., J.R.G.-J., J.S., D.P.-F., R.B., F.W., J.D., F.F.-A. and M.M.-S.; Formal Analysis, M.M.-S., and L.V.; Investigation, L.M.D., R.V.-G., J.R.G.-J., J.S., D.P.-F., R.B., F.W., J.D., F.F.-A. and M.M.-S.; Resources, R.V.-G., J.R.G.-J., J.S., D.P.-F., R.B., F.W., J.D., F.F.- A. and M.M.-S.; Data Curation, R.V.-G., J.R.G.-J., J.S., D.P.-F., R.B., F.W., J.D., F.F.-A. and M.M.-S.; Writing—Original Draft Preparation, L.V. and M.M.-S.; Writing—Review and Editing, L.V. and M.M.-S.; Visualization, R.V.-G., J.R.G.-J., J.S., D.P.-F., R.B., F.W., J.D., F.F.-A. and M.M.-S.; Supervision, R.V.-G., J.R.G.-J., J.S., D.P.-F., R.B., F.W., J.D., F.F.-A. and M.M.-S.; Project Administration, R.V.-G., J.R.G.-J., J.S., D.P.-F., R.B., F.W., J.D., F.F.-A. and M.M.-S.; Funding Acquisition, R.V.-G., J.R.G.-J., J.S., D.P.-F., R.B., F.W., J.D., F.F.-A. and M.M.-S. 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