ORIGINAL RESEARCH published: 25 February 2021 doi: 10.3389/fcvm.2021.630113 Influence of Gender in Advanced Heart Failure Therapies and Outcome Following Transplantation María Dolores García-Cosío 1,2*, Francisco González-Vilchez 3 , Raquel López-Vilella 4 , Eduardo Barge-Caballero 2,5 , Manuel Gómez Bueno 2,6 , Manuel Martínez-Selles 2,7 , Jose María Arizón 8 , Diego Rangel Sousa 9 , José González-Costello 10 , Sonia Mirabet 11 , Félix Pérez-Villa 12 , Beatriz Díaz Molina 13 , Gregorio Rábago 14 , Ana Portolés Ocampo 15 , Luis de la Fuente Galán 16 , Iris Garrido 17 and Juan F. Delgado 1,2,18 1 Servicio de Cardiología, Hospital 12 de Octubre Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain, 2 Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Madrid, Spain, 3 Servicio de Cardiología, Hospital Universitario Marqués de Valdecilla, Santander, Spain, 4 Servicio de Cardiología, Hospital Universitari i Politecnic La Fe, Valencia, Spain, 5 Servicio de Cardiología, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain, 6 Servicio de Cardiología, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain, 7 Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, Universidad Europea, Universidad Complutense, Madrid, Edited by: Spain, 8 Servicio de Cardiología, Hospital Universitario Reina Sofía, Cordoba, Spain, 9 Servicio de Cardiología, Hospital Chris J. Pemberton, Universitario Virgen Del Rocío, Seville, Spain, 10 Servicio de Cardiología, Hospital Universitari De Bellvitge, Hospitalet de University of Otago, New Zealand Llobregat, Spain, 11 Servicio de Cardiología, Hospital Santa Creu i Sant Pau, Barcelona, Spain, 12 Servicio de Cardiología, Reviewed by: Hospital Clínic i Provincial, Barcelona, Spain, 13 Servicio de Cardiología, Hospital Universitario Central De Asturias, Oviedo, Peter Ruygrok, Spain, 14 Servicio de Cirugía Cardiaca, Clínica Universidad De Navarra, Navarra, Spain, 15 Servicio de Cardiología, Hospital Auckland District Health Board, Universitario Miguel Servet, Zaragoza, Spain, 16 Servicio de Cardiología, Hospital Clínico Universitario De Valladolid, New Zealand Valladolid, Spain, 17 Servicio de Cardiología, Hospital Universitario Virgen De La Arrixaca, Murcia, Spain, 18 Departamento de Kristen M. Tecson, Medicina, Universidad Complutense de Madrid, Madrid, Spain Baylor Scott & White Research Institute (BSWRI), United States Biological differences between males and females change the course of different *Correspondence: María Dolores García-Cosío diseases and affect therapeutic measures’ responses. Heart failure is not an exception mariadolores.garcia-cosio@ to these differences. Women account for a minority of patients on the waiting list for salud.madrid.org heart transplantation or other advanced heart failure therapies. The reason for this under- representation is unknown. Men have a worse cardiovascular risk profile and suffer Specialty section: This article was submitted to more often from ischemic heart disease. Conversely, transplanted women are younger Heart Failure and Transplantation, and more frequently have non-ischemic cardiac disorders. Women’s poorer survival on a section of the journal Frontiers in Cardiovascular Medicine the waiting list for heart transplantation has been previously described, but this trend Received: 16 November 2020 has been corrected in recent years. The use of ventricular assist devices in women is Accepted: 12 January 2021 progressively increasing, with comparable results than in men. The indication rate for a Published: 25 February 2021 heart transplant in women (number of women on the waiting list for millions of habitants) Citation: has remained unchanged over the past 25 years. Long-term results of heart transplants García-Cosío MD, González-Vilchez F, López-Vilella R, Barge-Caballero E, are equal for both men and women. We have analyzed the data of a national registry of Gómez Bueno M, Martínez-Selles M, heart transplant patients to look for possible future directions for a more in-depth study María Arizón J, Rangel Sousa D, González-Costello J, Mirabet S, of sex differences in this area. We have analyzed 1-year outcomes of heart transplant Pérez-Villa F, Molina BD, Rábago G, recipients. We found similar results in men and women and no sex-related interactions Portolés Ocampo A, de la Fuente with any of the factors related to survival or differences in death causes between men Galán L, Garrido I and Delgado JF (2021) Influence of Gender in and women. We should keep trying to approach sex differences in prospective studies to Advanced Heart Failure Therapies and confirm if they deserve a different approach, which is not supported by current evidence. Outcome Following Transplantation. Front. Cardiovasc. Med. 8:630113. Keywords: gender, female, heart transplantation, outcome, women, advanced heart failure, ventricular assist doi: 10.3389/fcvm.2021.630113 device Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 February 2021 | Volume 8 | Article 630113 García-Cosío et al. Gender and Advanced Heart Therapies INTRODUCTION participating center. We excluded recipients of a second HT and multiorgan recipients. There is a growing interest in sex-related differences in several clinical scenarios. Men and women differ in body composition Missing Data and physiology; they present differences in pharmacokinetics Missing data (Supplementary Table 1) were handled by multiple and pharmacodynamics; and they may also respond differently imputations using the wholly conditional specification method, to cardiovascular drugs. Women are underrepresented in most generating 10 imputed datasets using all applicable adjustment clinical trials, and real-life data have shown that they are less often variables and the outcome variable as predictors. The average of treated with evidence-based therapies and experience adverse the 10 imputed data sets was used for analysis. For imputation, drug reactions more often (1). The reason for these differences categorical and continuous variables were modeled using logistic between men and women is beyond the scope of the present regression and linear regression, respectively. study. Still, a better knowledge of these sex-related differences may be helpful to improve patient care. Most heart failure (HF) patients are female. Women have Statistical Analysis a different clinical profile than men (2); they develop end- Quantitative variables were summarized as median (interquartile stage HF at an older age, have a higher prevalence of HF with range), and the Mann-Whitney U-test assessed between- preserved ejection fraction and a lower prevalence of ischemic sex differences. Categorical variables were summarized as heart disease (IHD) (3–5). HF prognosis seems to be better in percentages, with Chi-squared or Fisher’s exact tests, as women with a lower rate of premature death than men (4). appropriate, for between-sex comparisons. Moreover, in HF with reduced ejection fraction, women seem The primary outcome was 1-year all-cause mortality to have a better response to treatment, with a more favorable or re-transplantation. The associations between baseline reverse remodeling regardless of the cause and severity of the left population characteristics and outcome were fitted by the ventricle systolic dysfunction (5). In the field of advanced HF, the use of Cox proportional hazards regression. Multivariable underrepresentation of women among heart transplant (HT) or adjustment included the recipient’s sex and those variables ventricular assist devices (VAD) recipients has been attributed to with a significance level <0.10 in the univariable analysis. To selection and referral bias and potentially poorer outcomes for further explore possible differences between men and women, these therapies. However, whether the described better outcomes additional multivariable models were considered to include the in women with HF may also explain this under-representation in interaction between the recipient sex and each variable that advanced heart failure stages has not been explored. reached statistical significance in the final multivariable analysis. The majority of the studies in the field of heart transplantation All statistical tests were 2-sided, and a p-value <0.05 was (HT) are focused on donor-recipient mismatch (6–8). However, considered significant. All analyses were performed using the sex-related differences in patients on the waiting list for an HT or SPSS 25.0 (SPSS Inc., Chicago, IL). ventricular assist device and long term survival after an HT have been addressed recently. We aim to review those topics and look RESULTS for sex-related differences in 1-year outcomes after an HT in an extensive nationwide registry to elucidate possible gaps that may A total of 3,616 HT procedures were performed in 16 HT need further investigation in the future. centers during the study period. We identified 869 female recipients (24%). Sex-stratified baseline characteristics of the study population are shown in Table 1. MATERIALS AND METHODS Women were significantly younger, and had a lower body Data Source mass index and predicted heart mass than men. They also The Spanish Heart Transplant Registry is a prospective database presented with history of neoplastic disease more often. promoted by the Heart Failure Working Group of the Spanish Men had a poorer cardiovascular risk profile assessed as Society of Cardiology, containing detailed clinical information a higher prevalence of hypertension and diabetes, and triple about all HT procedures performed in our country from 1984 to the prevalence of peripheral artery disease. They also had two the present. The registry is updated yearly with data supplied by times the prevalence of chronic obstructive pulmonary disease. all transplant centers in the country (9). The Ethics Committees Men had undergone previous cardiac surgery more frequently of all participating centers have approved the Spanish Heart than women. Transplantation Registry for investigational purposes. HT indication was mainly due to IHD in men. Conversely, For the present study, we included all patients aged ≥18 in women, HT’s leading cause was dilated cardiomyopathy years who underwent an HT in Spain from January 1, 2005 (DCM), followed by other etiologies (valvular heart disease, to December 31, 2019. Vital status at the end of follow- congenital heart disease, hypertrophic cardiomyopathy, up and cause of death (when applicable) was known for all restrictive cardiomyopathy, and myocarditis). participants. The cause of death was locally adjudicated in each Urgent HT and mechanical circulatory support (VAD and intra-aortic balloon pump) were more frequent in men. Abbreviations: DCM, Dilated cardiomyopathy; HF, Heart Failure; HT, Heart Abnormal bilirubin levels and active infection at the moment of transplant; IHD, ischemic heart disease; VAD, Ventricular assist device. HT were also more frequent in men. Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 February 2021 | Volume 8 | Article 630113 García-Cosío et al. Gender and Advanced Heart Therapies TABLE 1 | Characteristics of the study cohort stratified by gender. Female Male P-value (n = 869) (n = 2,747) Recipient Age (years) 54.0 (43.0, 61.0) 57.0 (49.0, 63.0) <0.001 Etiology (%) <0.001 Dilated 38.7 36.4 Ischemic 22.8 45.0 Others 38.6 18.6 Predicted heart mass (g) 126.8 (118.1, 138.2) 176.0 (164.5, 189.2) <0.001 Body mass index (Kg/m2 ) 24.0 (21.3, 27.6) 25.5 (23.4, 28.2) <0.001 Diabetes (%) 12.1 23.3 <0.001 Hypertension (%) 23.2 38.9 <0.001 COPD (%) 6.1 12.2 < 0.001 Peripheral vascular disease (%) 2.6 7.8 <0.001 Pretransplant malignancy (%) 8.5 4.1 <0.001 GFR (ml/min/1.73 m2 ) 71.1 (51.4, 95.0) 71.3 (52.8, 94.5) 0.64 GFR < 45 mL/min/1.73 m2 17.6 15.0 0.08 CMV serology positive 82.3 80.0 0.15 Bilirubin >2 mg/dL 15.3 18.9 0.02 Pulmonary vascular resistance (WU) 2.0 (1.3, 2.9) 2.0 (1.3, 2.8) 0.42 Pre-transplant cardiac surgery (%) 25.3 29.2 0.03 Pre-transplant infection (%) 10.4 14.8 0.001 Pre-transplant mechanical ventilation (%) 15.5 14.4 0.44 Pre-transplant circulatory support (%) 0.002 None 71.1 65.6 IABP 11.1 13.0 ECMO 8.1 7.3 VAD 9.7 14.1 Recipient location (%) 0.08 Home 56.0 52.5 Hospital ward 11.4 10.7 Intensive care unit 32.6 36.8 Surgical procedure Urgent transplant (%) 33.8 37.9 0.03 Cold ischemic time (min) 210.0 (153.3, 240.0) 205.0 (155.0, 245.0) 0.94 Surgical technique (bicaval) (%) 61.0 64.3 0.08 Transplant era 0.34 2005–2009 31.4 33.7 2010–2014 30.1 30.3 2015–2019 38.4 36.0 Donor Age (years) 45.0 (34.0, 53.0) 44.0 (32.0, 52.0) 0.11 Gender (female) 57.3 28.7 <0.001 Predicted heart mass (g) 139.3 (129.0, 152.0) 184.0 (169.5, 199.0) <0.001 Body mass index (Kg/m2 ) 24.4 (22.5, 26.7) 26.0 (24.0, 28.4) <0.001 CMV serology positive 74.4 72.3 0.25 Cause of death (%) 0.02 Trauma 24.2 29.0 CVD 49.3 46.7 Other 26.6 24.3 Donor/recipient interaction Donor/recipient gender mismatch (%) 42.7 28.7 <0.001 (Continued) Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 February 2021 | Volume 8 | Article 630113 García-Cosío et al. Gender and Advanced Heart Therapies TABLE 1 | Continued Female Male P-value (n = 869) (n = 2,747) Donor/recipient predicted heart mass ratio 1.09 (1.00, 1.12) 1.03 (0.96, 1.13) <0.001 Donor/recipient CMV serology mismatch (%) 34.9 36.2 0.81 Donor/recipient BMI ratio 1.00 (0.89, 1.16) 1.01 (0.91, 1.14) 0.31 COPD, Chronic Obstructive Pulmonary Disease; GFR, Glomerular Filtration Rate; CMV, cytomegalovirus; WU, wood units; IABP, Intraaortic balloon pump; ECMO, extracorporeal membrane oxygenator; VAD, ventricular assist device; CVD, cerebrovascular disease. Although women received grafts from female donors who had interesting HF registries to gather information about HF patients’ a lower body mass index and predicted heart mass more often, clinical parameters and characteristics and their therapies, the donor/recipient sex mismatch was more frequent. Consequently, advanced heart failure population is somehow challenging to donor/recipient predicted heart mass ratio was higher. study and scarcely described in the literature. Gender differences Median follow-up was 1.01 years (interquartile range 0.71– in HF patients have been previously described, but their clinical 1.01). Results of the univariate and multivariate Cox regression implications remain unclear. A better knowledge of the sex- analysis are summarized in Table 2. Variables related to impaired related differences appears as a potential field of improvement survival included recipient age, higher body mass index, diabetes in the diagnosis, treatment, and likely prognosis of HF patients. mellitus, bilirubin of >2 mg/dl, pre-HT infection, previous The more significant publications addressing sex differences cardiac surgery, need for mechanical ventilation at the moment in advanced HF patients (waiting-list, HT, and VAD) are of HT, mechanical circulatory support at the time of HT, recipient summarized in Table 4. location in the Intensive Care Unit, urgent transplant, cold Previous studies with a small sample of patients showed ischemic time, female donor and donor/recipient sex mismatch, a worse survival rate for women on the waiting list for HT and donor/recipient body mass index ratio. Higher glomerular (19). Several analyses of the Scientific Registry of Transplant filtration rate, bicaval surgical technique, and HT in the recent Recipients of the United States of America have assessed the same period (2015–2019) were related to a better outcome. After topic. Hsich et al. in 2014 analyzed sex differences in patients multivariate analysis, body mass index and diabetes of the listed for HT in 10 years (2000–2010) stratified by severity of recipient lost statistical significance as did any type of mechanical illness (1A, high risk; 1B, intermediate risk; and 2, low-risk circulatory support at the time of HT, recipient location at the ambulatory patients) and adjusted by baseline characteristics. time of HT, urgent status, female donor, and donor-recipient Women accounted for 25% of the study population, and they body mass index. had a higher mortality rate than men in urgent status (1A) but In the final model, variables independently related to reduced a lower mortality rate than men in an elective ambulatory setting survival were recipient age, history of previous cardiac surgery, (status 2). No differences were observed in the intermediate-risk bilirubin of >2 mg/dl, pre-HT infection, need for mechanical status 1B (11). Women were younger and had a non-ischemic ventilation at the moment of HT, cold ischemic time, and cardiomyopathy more often, and men had a worse cardiovascular donor/recipient sex mismatch. Higher glomerular filtration rate, risk profile, and IHD was the leading cause for HF. The same bicaval surgical technique, and HT in the recent period (2015– authors tried to confirm these sex differences in a more recent 2019) were independently associated with a better prognosis. period (2004–2015) and attempted to identify factors associated Women and men had a similar 1-year survival (women 76.4 with waiting-list mortality and transplantation timing. Although vs. 78.6% men p = 0.34) by adjusted Kaplan-Meier analysis similar differences in mortality were observed between 2004 and (Figure 1). We did not find any differences in the cause of death 2008 (higher mortality in woman in status 1A and 1B and lower between men and women (Figure 2). in status 2), in the most recent years, some of them were solved, We did not find any interaction between sex and variables and women had a similar survival in urgent status (1A) and independently related to survival in the multivariate analysis elective status (2). They also identified many sex interactions (Table 3). for death and HT that varied with prioritization on the waiting list that should be addressed as a new field to understand these differences between men and women (12). Improvements in the DISCUSSION risk of death or deterioration in women waiting for HT have also been observed in other studies (20). Advanced heart failure affects 1–10% of the overall HF There is also available information about sex-related population and implies a severe decline in patients’ quality of differences in VAD therapy. As expected, baseline characteristics life and survival. The Heart Failure Association of the European and underlying comorbidities and etiologies differed between Society of Cardiology has recently updated diagnostic criteria. It men and women as it has been described for studies of patients focuses on patient referral to advanced HF centers and a proper on the HT waiting list. An analysis of the European Registry transition of patients to palliative care (10). Although there are for Patients with Mechanical Circulatory Support showed that Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 February 2021 | Volume 8 | Article 630113 García-Cosío et al. Gender and Advanced Heart Therapies TABLE 2 | Uni- and multivariate Cox regression analysis of 1-y survival. Univariate Multivariate HR CI (95%) P-value HR CI (95%) P-value Recipient Female gender 1.11 0.94–1.30 0.21 1.15 0.97–1.36 0.10 Age (years) 1.01 1.01–1.02 <0.001 1.01 1.00–1.02 0.005 Predicted heart mass (g) 1.00 1.00–1.00 0.59 Body mass index (Kg/m2 ) 1.02 1.00–1.04 0.02 1.01 0.97–1.03 0.68 Etiology Dilated 1 Ischemic 1.11 0.94–1.30 0.22 Other 1.16 0.97–1.40 0.11 Diabetes 1.18 1.00–1.40 0.05 1.11 0.93–1.33 0.23 Hypertension 1.13 0.98–1.32 0.10 COPD 1.09 0.87–1.36 0.48 PVD 1.20 0.92–1.56 0.18 GFR (mL/min/1.73 m2 ) 0.99 0.99–0.99 <0.001 0.99 0.99–1.00 <0.001 CMV serology positive 1.10 0.92–1.33 0.29 Bilirubin >2 mg/dL 1.49 1.25–1.78 <0.001 1.35 1.13–1.61 0.001 PVR (Wood U.) 1.05 1.00–1.11 0.08 1.02 0.97–1.08 0.42 Pre-transplant infection 1.60 1.34–1.92 <0.001 1.34 1.10–1.63 0.004 Pre-transplant cardiac surgery 1.32 1.14–1.53 <0.001 1.22 1.04–1.43 0.02 Mechanical ventilation 2.00 1.70–2.37 <0.001 1.64 1.32–2.05 <0.001 Pre-transplant circulatory support None 1 1 IABP 1.45 1.18–1.77 <0.001 1.10 0.88–1.37 0.41 ECMO 1.69 1.34–2.15 <0.001 1.20 0.89–1.63 0.23 VAD 1.39 1.14–1.71 0.001 1.21 0.94–1.57 0.15 Recipient locationa Home 1 Hospital ward 1.15 0.90–1.46 0.27 Intensive care unit 1.57 1.35–1.82 <0.001 Pre-transplant malignancy (%) 1.19 0.89–1.61 0.24 Surgical procedure Urgent transplant 1.51 1.31–1.74 <0.001 Cold ischemic time (min) 1.00 1.00–1.00 <0.001 1.00 1.00–1.00 <0.001 Surgical technique (bicaval) (%) 0.78 0.68–0.90 0.001 0.85 0.73–0.99 0.03 Transplant era 2005–2009 1 1 2010–2014 0.90 0.76–1.07 0.24 0.91 0.77–1.09 0.30 2015–2019 0.72 0.61–0.86 <0.001 0.70 0.58–0.85 <0.001 Donor Age (years) 1.00 1.00–1.01 0.22 Gender femalea 1.20 1.07–1.34 0.001 Predicted heart mass (g) 1.00 1.00–1.00 0.33 Body mass index (Kg/m2 ) 0.99 0.98–1.01 0.50 Cause of death Trauma 1 CVD 0.95 0.81–1.13 0.56 Other 1.00 0.83–1.21 0.99 CMV serology positive 0.88 0.75–1.04 0.12 Donor/recipient interaction (Continued) Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 February 2021 | Volume 8 | Article 630113 García-Cosío et al. Gender and Advanced Heart Therapies TABLE 2 | Continued Univariate Multivariate HR CI (95%) P-value HR CI (95%) P-value Donor/recipient gender mismatch 1.16 1.00–1.34 0.049 1.22 1.05–1.42 0.01 Recipient/Donor CMV mismatch No 1 Donor (−)/recipient (+) 1.14 0.96–1.37 0.14 Donor (+)/recipient (−) 0.91 0.73–1.15 0.43 Donor/recipient predicted heart mass ratio 0.92 0.55–1.54 0.75 Donor/recipient body mass index ratio 0.65 0.45–0.95 0.02 0.80 0.50–1.28 0.35 HR, Hazard ratio; CI, Confidence interval; COPD, Chronic obstructive pulmonary disease; CVD, cerebrovascular disease; ECMO, extracorporeal membrane oxygenator; GFR, glomerular filtration rate; IABP, intra-aortic balloon pump; PVD, peripheral vascular disease; PVR, pulmonary vascular resistance; VAD, ventricular assist device. a Urgent transplant, recipient location, and donor sex were not included in the multivariate model due to collinearity with Pre-transplant Circulatory Support and recipient and donor sex. FIGURE 1 | Adjusted 1-year survival curves according to recipient sex. only 15% of patients receiving a VAD were women. HT rates severe HF, but a similar adverse event rate. Those differences were similar for men and women. However, women were at a in outcomes may reflect different follow-up times and, thus, more advanced stage at the moment of implantation, presented different rates of adverse events in men and women after a higher rate of significant bleeding, arrhythmias, and right perioperative period. ventricular failure, and had a worse prognosis than men (13). Several factors might play a role in sex-related differences Two studies in the United States of America also showed a in HT outcomes: the higher frequency of anti-HLA antibodies lower use of VAD in women, although slightly higher than in detection in women, differences in predicted heart mass as a the European Registry (21–23%). This higher percentage of critical factor in donor-recipient matching, and variability in women undergoing a VAD implantation might be explained clinical presentation men and women (21, 22). The New Heart by the inclusion of patients listed in a more recent time-lapse. study was the first one to address this topic. They found a similar Increasing use of VAD therapy in women throughout the survival for HT in women, who represented 28% of the analyzed observation period is described. Both American registries population. Conversely, women were younger and developed represent conflicting results on survival. The former is focused graft rejection and needed hospitalization more often than men on in-hospital survival and showed similar survival for men (16). An analysis of the International Society of Heart and Lung and women (15). The latter evaluated more extended follow-up Transplantation Registry, in which 23.7% of included patients periods and described lower HT rates and a lower survival in were women, also showed similar survival rates after adjusting by women (14). In both registries, women presented with a more recipient and donor risk scores but suggested a higher mortality Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 February 2021 | Volume 8 | Article 630113 García-Cosío et al. Gender and Advanced Heart Therapies FIGURE 2 | Causes of death segregated by sex. Data are expressed as count (percentage in the y-axis). Chi-square = 6.075; P = 0.41. TABLE 3 | Analysis of interactions between recipient gender and significant variables in multivariate analysis. Variable Recipient female gender Interaction recipient sex * variable HR CI (95%) P-value HR CI (95%) P-value Recipient age 0.83 0.36–1.90 0.66 1.01 0.99–1.02 0.46 GFR (mL/min/1.73 m2 ) 1.01 0.64–1.60 0.95 1.00 0.99–1.01 0.64 Bilirubin >2 mg/dL 1.08 0.89–1.30 0.43 1.21 0.81–1.79 0.35 Pre-transplant infection 1.07 0.89–1.28 0.49 1.34 0.89–2.04 0.17 Pre-transplant cardiac surgery 1.08 0.88–1.31 0.47 1.14 0.81–1.61 0.46 Mechanical ventilation 1.11 0.92–1.34 0.30 1.06 0.73–1.54 0.76 Bicaval surgical technique 1.22 0.95–1.55 0.12 0.87 0.62–1.20 0.39 Cold ischemic time 0.81 0.46–1.44 0.47 1.00 1.00–1.00 0.24 Transplant era 1.04 0.79–1.37 0.76 2010–2014 1.20 0.81–1.77 0.37 2015–2019 1.05 0.70–1.56 0.81 Donor/Recipient gender mismatch 1.11 0.89–1.38 0.35 1.03 0.74–1.43 0.88 GFR, glomerular filtration rate. Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 February 2021 | Volume 8 | Article 630113 García-Cosío et al. Gender and Advanced Heart Therapies TABLE 4 | Summary of recent publications addressing gender differences in patients on the waiting for a heart transplant, receiving a long term ventricular assist device, or heart transplant recipients. Publication Population Period Analysis Conclusions Hsich et al. (11) 28852 PWL 2000–2010 Propensity Score Women higher risk in urgent status 24% women Long term survival Similar results in intermediate status in men and women (SRTR) Men higher risk in elective status Hsich et al. (12) 33069 PWL 2004–2015 3 year survival Higher risk in urgent and intermediate status in women, 25% women Random survival forest similar in recent period (SRTR) Higher risk in elective status in men Multiple interactions between sex in different status Magnussen et al. (13) 966 VAD (75% BTT) 2011–2014 1–2-year survival Similar HT rates 15% women Women worse survival (EUROMACS) Women sicker at implant Women higher major bleeding, arrhythmias, and RV failure DeFilippis et al. (14) 13305 VAD 2008–2018 Propensity Score Increase in VAD use among decade (lower in women) 20.8% women 1-2-year survival Women sicker at implant, similar complications (UNOS) Women lower HT rate and survival Ahmed et al. (15) 3511 VAD 2009–2014 Propensity Score Similar survival 23.3% women In hospital survival Similar complications (NIS) VAD in females have doubled lately Hickey et al. (16) 345 HT 2011–2015 1-year survival Similar survival 28% women Women younger NEW HEART study Women more rejection episodes and hospitalizations Moayedi et al. (17) 34198 HT 2004–2014 Propensity Score Similar survival 23.7% women Adjusted IMPACT / DRI Lowest survival in undersized donors (ISHLTR) Long-term survival Women higher mortality in regular sized donors García-Cosío et al. (18) 6740 HT 1997–2017 Temporal trends Similar survival 20.6% women Transplant rate pmh Similar HT pmh in women among 25 years (lower in men) (SHTR) Long term survival Women died due to rejection and primary graft failure Men died due to malignancies Current series 3616 HT 2005–2019 1-year survival Similar survival 24% women (SHTR) PWL, Patients on the waiting list; SRTR, USA Scientific Registry of Transplant Recipients; VAD, long term ventricular assist device; BTT, bridge to transplantation; EUROMACS, European Registry for Patients with Mechanical Circulatory Support; HT, Heart transplant; RV, right ventricle; UNOS, United Network for Organ Sharing; NIS, USA National Inpatient Database; ISHLTR, International Society of Heart and Lung Transplantation Registry; IMPACT, Index for Mortality Prediction After Cardiac Transplantation score; DRI, Donor Risk Index; SHTR, Spanish Heart Transplant Registry; Pmh, per million habitants. rate to women who received a graft of a regular-sized donor results in men and women, we cannot extrapolate our results to (17). Our previous work analyzing the Spanish Heart Transplant other populations with a higher VAD use. Urgent HT was more Registry results over the last 25 years showed a similar survival frequent in men, but it was not associated with higher mortality and similar HT rate in women per million habitants. Causes of after multivariate analysis. We cannot determine whether this death differed between men, mainly due to neoplastic diseases, difference is influenced by a higher delisting rate of women due and women, mainly due to primary graft failure and rejection to clinical deterioration before HT or different use of therapies (18). All the described studies show a comparable pattern of that determine urgent status in our country (i.e., intra-aortic baseline characteristics and underlying heart disease. balloon pump until 2015, extracorporeal membrane oxygenator, Our study aims to describe sex-related differences in 1-year or VAD). outcomes after an HT in a contemporary cohort. Given that To conclude, despite sex-related differences in the clinical previous studies showed sex-related differences in higher-risk profile and the donor-recipient matching, 1-year outcomes are recipients, we sought to analyze 1-year HT results as they may comparable. We did not find differences in the cause of death, be affected considerably by perioperative factors like the patient’s and we did not find any interactions between sex and factors clinical situation on the waiting list or the etiology of HF. significantly associated with differences in survival. We did not find differences in the recipient’s location (outpatient or hospitalized) at the time of HT. The need for LIMITATIONS circulatory support at the moment of HT was more frequent in men (mainly VAD), but it was not associated with different Our analysis of 1-year outcomes after HT has some limitations outcomes. VADs were used in a low percentage of HT candidates that must be acknowledged. The main limitation is the lack of in our cohort. Given that VAD therapy may have different information about patients included on the waiting list for HT Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 February 2021 | Volume 8 | Article 630113 García-Cosío et al. Gender and Advanced Heart Therapies since the patient’s follow-up begins at HT. Thus, we do not have AUTHOR CONTRIBUTIONS any data about those patients who are included on the waiting list and are delisted or died before HT. Another limitation is the low MG-C, JD, and FG-V have contributed to the conception and rate of VAD implantation in our cohort that prevents us from design of the work. MG-C and FG-V have contributed to the extrapolating these results to other populations. Furthermore, analysis and interpretation of the work’s data and drafting. the retrospective nature of a registry analysis also constitutes a BM, RL-V, EB-C, MG, MM-S, JM, DR, JG-C, SM, FP-V, significant limitation. GR, AP, LdlF, and IG have contributed in revising the article critically. All authors contributed to the article and approved the CONCLUSION submitted version. Women are under-represented in the waiting list for an HT FUNDING or a VAD. Although clinical profile and HF etiology differ between men and women, overall survival and complications This investigation was funded by Centro de Investigación en are similar. It is desirable to study sex-related differences to Red de Enfermedades Cardiovasculares (CIBERCV), Instituto understand if we should adjust clinical protocols in advanced HF de Salud Carlos III, and Spanish Ministry of Economy patients by sex. and Competitiveness. DATA AVAILABILITY STATEMENT ACKNOWLEDGMENTS The raw data supporting the conclusions of this article will be We would like to acknowledge all people involved in the made available by the authors, without undue reservation. conception, development, and maintenance of the Spanish Heart Transplantation Registry. ETHICS STATEMENT SUPPLEMENTARY MATERIAL Ethical review and approval was not required for the study on human participants in accordance with the local legislation and The Supplementary Material for this article can be found institutional requirements. The patients/participants provided online at: https://www.frontiersin.org/articles/10.3389/fcvm. their written informed consent to participate in this study. 2021.630113/full#supplementary-material REFERENCES 9. González-Vílchez F, Gómez-Bueno M, Almenar-Bonet L, Crespo-Leiro MG, Arizón del Prado JM, Delgado-Jiménez J, et al. Registro Español de Trasplante 1. Tamargo J, Rosano G, Walther T, Duarte J, Niessner A, Kaski JC, et al. Cardiaco. XXVIII Informe Oficial de la Sección de Insuficiencia Cardiaca de la Gender differences in the effects of cardiovascular drugs. Eur Hear J. (2017) Sociedad Española de Cardiología (1984–2016). Rev Española Cardiol. (2017) 3:163–82. doi: 10.1093/ehjcvp/pvw042 70:1098–109. doi: 10.1016/j.recesp.2017.07.032 2. Crespo Leiro MG, Paniagua Martín MJ. Heart failure. Are women different? 10. Crespo-Leiro MG, Metra M, Lund LH, Milicic D, Costanzo MR, Filippatos Rev Esp Cardiol. (2006) 59:725–35. doi: 10.1016/S1885-5857(07)60031-0 G, et al. Advanced heart failure: a position statement of the Heart Failure 3. Dunlay SM, Roger VL. Gender differences in the pathophysiology, clinical Association of the European Society of Cardiology. Eur J Heart Fail. (2018) presentation, and outcomes of ischemic heart failure. Curr Heart Fail Rep. 20:1505–35. doi: 10.1002/ejhf.1236 (2012) 9:267–76. doi: 10.1007/s11897-012-0107-7 11. Hsich EM, Starling RC, Blackstone EH, Singh TP, Young JB, Gorodeski 4. Gómez-Martínez L, Orozco-Beltrán D, Quesada JA, Bertomeu-González V, EZ, et al. Does the UNOS heart transplant allocation system favor men Gil-Guillén VF, López-Pineda A, et al. Trends in premature mortality due over women? JACC Hear Fail. (2014) 2:347–55. doi: 10.1016/j.jchf.2014. to heart failure by autonomous community in Spain: 1999 to 2013. Rev Esp 03.008 Cardiol. (2018) 71:531–7. doi: 10.1016/j.rec.2017.09.026 12. Hsich EM, Blackstone EH, Thuita L, McNamara DM, Rogers JG, Ishwaran 5. Aimo A, Vergaro G, Castiglione V, Barison A, Pasanisi E, Petersen C, et al. H, et al. Sex differences in mortality based on united network for organ Effect of sex on reverse remodeling in chronic systolic heart failure. JACC Hear sharing status while awaiting heart transplantation. Circ Hear Fail. (2017) Fail. (2017) 5:735–42. doi: 10.1016/j.jchf.2017.07.011 10:e003635. doi: 10.1161/CIRCHEARTFAILURE.116.003635 6. Martinez-Selles M, Almenar L, Paniagua-Martin MJ, Segovia J, Delgado 13. Magnussen C, Bernhardt AM, Ojeda FM, Wagner FM, Gummert JF, Arizón JM, et al. Donor/recipient sex mismatch and survival after J, de By TMMH, et al. Gender differences and outcomes in left heart transplantation: only an issue in male recipients? an analysis of ventricular assist device support: the European Registry for Patients the Spanish Heart Transplantation Registry. Transpl Int. (2015) 28:305– with Mechanical Circulatory Support. J Hear Lung Transplant. (2018) 13. doi: 10.1111/tri.12488 37:61–70. doi: 10.1016/j.healun.2017.06.016 7. Khush KK, Kubo JT, Desai M. Influence of donor and recipient sex mismatch 14. DeFilippis EM, Truby LK, Garan AR, Givens RC, Takeda K, Takayama on heart transplant outcomes: analysis of the International Society for Heart H, et al. Sex-related differences in use and outcomes of left ventricular and Lung Transplantation Registry. J Hear Lung Transplant. (2012) 31:459– assist devices as bridge to transplantation. JACC Hear Fail. (2019) 7:250– 66. doi: 10.1016/j.healun.2012.02.005 7. doi: 10.1016/j.jchf.2019.01.008 8. Kaczmarek I, Meiser B, Beiras-Fernandez A, Guethoff S, Überfuhr P, 15. Ahmed A, Adegbala O, Akintoye E, Inampudi C, Ajam M, Yassin Angele M, et al. Gender does matter: gender-specific outcome analysis AS, et al. Gender differences in outcomes after implantation of 67,855 heart transplants. Thorac Cardiovasc Surg. (2013) 61:29– of left ventricular assist devices. Ann Thorac Surg. (2020) 36. doi: 10.1055/s-0032-1331467 109:780–6. doi: 10.1016/j.athoracsur.2019.07.032 Frontiers in Cardiovascular Medicine | www.frontiersin.org 9 February 2021 | Volume 8 | Article 630113 García-Cosío et al. Gender and Advanced Heart Therapies 16. Hickey KT, Doering LV, Chen B, Carter EV, Sciacca RR, the modern era. J Card Fail. (2015) 21:555–60. doi: 10.1016/j.cardfail.2015. Pickham D, et al. Clinical and gender differences in heart 03.009 transplant recipients in the NEW HEART study. Eur J 21. Kransdorf EP, Kittleson MM, Benck LR, Patel JK, Chung JS, Cardiovasc Nurs. (2017) 16:222–9. doi: 10.1177/14745151166 Esmailian F, et al. Predicted heart mass is the optimal metric for 51178 size match in heart transplantation. J Hear Lung Transplant. (2019) 17. Moayedi Y, Fan CPS, Cherikh WS, Stehlik J, Teuteberg JJ, Ross HJ, et al. 38:156–65. doi: 10.1016/j.healun.2018.09.017 Survival outcomes after heart transplantation: does recipient sex matter? 22. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Circ Heart Fail. (2019) 12:e006218. doi: 10.1161/CIRCHEARTFAILURE.119. Immunol. (2016) 16:626–38. doi: 10.1038/nri.2016.90 006218 18. García-Cosío MD, González-Vilchez F, López-Vilella R, Barge-Caballero E, Conflict of Interest: The authors declare that the research was conducted in the Gómez-Bueno M, Martínez-Selles M, et al. Gender differences in heart absence of any commercial or financial relationships that could be construed as a transplantation: Twenty-five year trends in the nationwide Spanish heart potential conflict of interest. transplant registry. Clin Transplant. (2020) 2020:e14096. doi: 10.1111/ctr. 14096 Copyright © 2021 García-Cosío, González-Vilchez, López-Vilella, Barge-Caballero, 19. Weidner G, Zahn D, Mendell NR, Smits JMA, Deng MC, Gómez Bueno, Martínez-Selles, María Arizón, Rangel Sousa, González-Costello, Zittermann A, et al. Patients’ sex and emotional support as Mirabet, Pérez-Villa, Molina, Rábago, Portolés Ocampo, de la Fuente Galán, predictors of death and clinical deterioration in the waiting Garrido and Delgado. This is an open-access article distributed under the terms for a new heart study: results from the 1-year follow-up. Prog of the Creative Commons Attribution License (CC BY). The use, distribution or Transplant. (2011) 21:106–14. doi: 10.7182/prtr.21.2.j779w1q6k61k reproduction in other forums is permitted, provided the original author(s) and the 0jk4 copyright owner(s) are credited and that the original publication in this journal 20. Morris AA, Cole RT, Laskar SR, Kalogeropoulos A, Vega JD, Smith A, is cited, in accordance with accepted academic practice. No use, distribution or et al. Improved outcomes for women on the heart transplant wait list in reproduction is permitted which does not comply with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 10 February 2021 | Volume 8 | Article 630113