Gender-related differences in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) affects more women than men, suggesting gender to play a major role in disease evolution. However, studies investigating gender differences in HFpEF are limited. In the present study we aimed to describe gender differences in a well-characterized HFpEF cohort. Consecutive HFpEF patients underwent invasive hemodynamic assessment, cardiac magnetic resonance imaging and exercise testing. Study endpoints were: cardiac death, a combined endpoint of HF hospitalization or cardiac death and all-cause death. 260 HFpEF patients were prospectively enrolled. Men were more compromised with regard to exercise capacity and had significantly more co-morbidities. Men had more pronounced pulmonary vascular disease with higher diastolic pressure gradients and a lower right ventricular EF. During follow-up, 9.2% experienced cardiac death, 33.5% the combined endpoint and 17.3% all-cause death. Male gender was independently associated with cardiac death, but neither with the combined endpoint nor with all-cause mortality. We detected clear gender differences in HFpEF patients. Cardiac death was more common among men, but not all-cause death. While men are more prone to develop a right heart phenotype and die from HFpEF, women are more likely to die with HFpEF.


Invasive hemodynamic parameters
Mean pulmonary arterial pressure, mmHg 33  Inclusion criteria for this study were [1] signs or symptoms of HF, [2] LVEF ≥ 50%, [3] N-terminal prohormone of brain natriuretic peptide (NT-proBNP) > 220 pg/mL, and [4] evidence of LV diastolic dysfunction by transthoracic echocardiography (TTE). LV diastolic dysfunction was assessed via the ratio of early transmitral blood velocity (E) to early diastolic mitral annular velocity (e'). Diastolic dysfunction was diagnosed, if E/e' was > 15. Patients with E/e' between 8-15 represented intermediate cases in whom diastolic dysfunction was considered, but could neither be confirmed nor excluded. Diastolic dysfunction was excluded in patients with E/e' ≤ 8. If diastolic dysfunction and HFpEF were likely after TTE and NT-proBNP assessment, right heart catheterization was performed in order to confirm the diagnosis. The diagnosis was confirmed, if pulmonary artery wedge pressure (PAWP) was >12 mmHg 12 .
Main exclusion criteria were significant CAD, which was assessed by coronary angiography and defined as a visual stenosis over 50% in one of the main vessels and/or over 70% in one of the distal vessels, significant valvular or congenital heart disease, severe chronic obstructive lung disease (COPD) (Global Initiative for Chronic Obstructive Lung Disease grade III or IV) and cardiac amyloidosis. Cardiac amyloidosis was diagnosed in accordance with current recommendations using cardiac magnetic resonance imaging (CMR), 99 mTc-3,3-d iphosphono-1,2-propanodicarboxylic acid scintigraphy, serum and urine immunofixation and if necessary, endomyocardial biopsy 13 . Outcomes. Three different endpoints were assessed: [1] cardiac death, [2] cardiac death or HF hospitalization and [3] all-cause death. To ascertain study endpoints, patients were followed via outpatient visits or telephone calls in case of immobility. If an event occurred, local and external medical records as well as conversations with the patients and/or their relatives were used for preparation of endpoint-reports, which were reviewed by a clinical adjudication committee (D.B, S.A, J.M).
Death from right heart failure (RHF) was defined as follows: [1] Presence of right ventricular (RV) dysfunction on TTE and/or CMR. RV dysfunction on echocardiography was defined as tricuspid annular plane systolic excursion (TAPSE) < 16 mm and/or RV fractional area change (FAC) < 35%. Parameters were measured according to current guidelines 14 . RV dysfunction was confirmed on CMR, if RVEF was < 45% 15 . [2] Presence of clinical signs and symptoms of RHF such as dyspnea, peripheral edema, ascites, elevation of liver enzymes or jugular venous distension at time of death. Sudden cardiac death (SCD) was defined as sudden, unexpected death from cardiac arrhythmia (documented on ECG) without prior circulatory failure, or in case of out-of-hospital SCD, death following an unexpected, sudden collapse without pulse or respiration in the absence of an obvious non-cardiac reason.
Cardiac magnetic resonance imaging. Patients without contraindications underwent CMR on a 1.5 Tesla scanner (MAGNETOM Avanto, Siemens Healthcare GmbH, Erlangen, Germany). All CMR studies were performed according to standard protocols including functional and late gadolimium enhancement imaging 16 . Transthoracic echocardiography. All patients underwent TTE on high-end scanners (GE Vivid 5 and Vivid 7; GE Healthcare, Wauwatosa, WI, USA). All examinations were performed by board-certified physicians. in accordance with current guidelines 14,17 . Parameters of interest were E/e' , TAPSE, FAC, degree of tricuspid regurgitation and sPAP. Moderate or severe tricuspid regurgitation were considered significant 18 . Furthermore, the ratio between TAPSE and sPAP was assessed in order to characterize RV function with an afterload-independent parameter 19 .   Table 3. Univariable and multivariable Cox regression analyses for the endpoint cardiac death. NYHA indicates New York Heart Association; NT-proBNP, N-terminal prohormone of brain natriuretic peptide. *NT-proBNP was graded into quintiles. † Patients with severe chronic obstructive pulmonary disease (GOLD ≥ III) were excluded from the registry. Baseline characteristics. Baseline characteristics for the study cohort are displayed in Table 1 co-morbidities such as arterial hypertension, morbid obesity, atrial fibrillation, chronic kidney disease, or diabetes mellitus type II were frequently present. Furthermore, pulmonary hypertension (PH) was frequent (71.9%) among study participants. 59.6% had isolated post-capillary pulmonary hypertension (IpcPH) and 12.3% had combined post-and pre-capillary pulmonary hypertension (CpcPH). Of the 260 HFpEF patients, 181 (69.6%) were female and 79 (30.4%) were male. Median age of female study participants was 73.0 years (IQR: 67.5-77.0) and 72.0 years (IQR: 66.0-77.0) in men (p = 0.237). Concomitant medications were equally distributed between men and women. Furthermore, men were more often current/ former smokers (40.5% versus 23.8%, p = 0.009). Relevant gender differences were encountered with respect to cardiac and hemodynamic parameters. Compared to female patients, men had higher DPG  (Table 1). Men had higher rates of cardiac death (16.5% versus 6.1%, p = 0.008) and lower rates of non-cardiac death (2.5% versus 10.5%, p = 0.030) as compared to women (Table 1). Women more often died from infections (23.3% versus 0.0%, p = 0.042), whereas RHF (73.3% versus 36.7%, p = 0.020) and SCD (13.3% versus 0.0%, p = 0.041) were more frequent among men ( Table 2).
Uni-and multivariable Cox regression analyses for the HFpEF cohort are shown in Table 3, Supplemental Tables 1 and 2. In uni-and multivariable Cox regression as well as Kaplan-Meier analyses, male gender was independently associated with shorter time to cardiac death [hazard ratio (HR): 2.639, confidence interval (CI): 1.023-6.805, p = 0.045, Table 3, Fig. 1A]. In addition, male HFpEF patients reached the combined endpoint within a shorter time period as compared to their female counterparts (HR: 1.588, 95% CI: 1.029-2.450, p = 0.037, Supplemental Table 1, Fig. 1B). In the multivariable analysis including clinical parameters such as exercise capacity and NT-proBNP, male gender itself failed to predict event-free survival for the combined endpoint (Supplemental Table 1). There was no difference with regards to time to all-cause death between the two groups (HR: 1.164, 95% CI: 0.626-2.164, p = 0.631, Supplemental Table 2, Fig. 1C).

Discussion
Gender-related differences in heart failure with preserved ejection fraction. Epidemiological studies suggest that gender plays an important role in the development of HFpEF, which is reflected by a female predominance in this disease with a gender ratio of approximately 2:1 4,21 . In fact, a relatively large body of evidence suggests that women are more prone to develop a hypertrophied, stiff and non-dilated LV, which is pathognomonic for HFpEF 22,23 . Despite the fact that gender seems to play quite an important role for HFpEF evolution, only few studies have specifically investigated gender-related differences in pure HFpEF cohorts 6,7 .
Among the studies that have, it could be shown that women tend towards higher LVEF, worse diastolic function and less co-morbid conditions as compared to men 6,7 . However, despite their prognostic importance in HFpEF, PAP, RV function and exercise capacity have not been systematically assessed within the context of a HFpEF gender study 15,[24][25][26] . In the present study, we have performed invasive hemodynamic assessment and CMR studies, which are the current gold standard for characterization of hemodynamics and cardiac function.
Results from the I-Preserve trial, which included roughly 3000 HFpEF patients detected a worse outcome for male HFpEF patients, who had a higher risk for all-cause death 6 . This stands in contrast to the results from the present study, where gender was not predictive for this endpoint. This difference might be attributable to the fact that we have actively screened for and excluded significant CAD as well as cardiac amyloidosis. These conditions are associated with male gender, poor outcomes and could, if not ruled out, mimic HFpEF 9,29 . A recent publication by Hoeper and colleagues investigating 108 patients with HFpEF and subsequent pulmonary hypertension (PH) also found male gender to be an independent predictor of all-cause death 28 . However, Hoeper et al. only studied patients with PH-HFpEF and the present study included HFpEF patients with and without PH. This difference between the study populations could explain why male gender was not associated with all-cause mortality in our study.
Gender and mode of death in heart failure with preserved ejection fraction. In the present study, mode of death (MOD) differed significantly between male and female HFpEF patients. Men almost exclusively died from RHF (73.3%) and SCD (13.3%), whereas MOD was more diverse among women (RHF: 36.7%, infection: 23.3%, malignancy: 13.3%). A recently published review investigated MOD of HFpEF patients in clinical trials as well as epidemiological studies 30 . By contrast to the existing literature, where the reported MOD was cardiovascular in more than two thirds of HFpEF patients, our results suggest a considerably higher rate of non-cardiovascular deaths 10,30 . One explanation for this discrepancy could be the enrichment of male participants in clinical HFpEF trials (Charm Preserved: 60%, Topcat: 52%, I-Preserve: 60%) 31-33 compared to our all-comers registry (30.4%). Further explanations for these differences could be a lack of standardized definitions for MOD, different LVEF cutoffs across studies (Charm Preserved: > 40%, Topcat: ≥ 45%, I-Preserve: ≥ 45% versus ≥ 50% in the present study) [31][32][33] , younger patients populations in clinical trials (Charm Preserved: 67.2 ± 11.1 years, Topcat: 68.7 years IQR: 60.7-75.5, I-Preserve: 72.0 years ± 7.0 versus 73.0 years IQR: 67.0-77.0 in the present study) [31][32][33] , thus reducing the risk for non-cardiovascular deaths such as infections or malignancies.

Limitations.
One limitation of the present study is its single-center design. Even though a center-specific bias cannot be excluded, limiting data collection to one center has the advantage of a constant clinical work-up, constant clinical routine and constant follow-up. Compared to previous trials investigating gender differences, our study cohort is relatively small and the number of events is limited 6 . Furthermore, the duration of HF before patient enrollment has not been assessed. However, due to the systematic use of left-and right heart catheterization as well as CMR imaging we were able to study a very well-characterized pure HFpEF population.

Conclusions
In this prospective study of a well-characterized HFpEF cohort we could demonstrate clear differences between male and female HFpEF patients. Men were more compromised with respect to clinical, functional and hemodynamic parameters, which seemed to explain worse cardiac outcome among them. Differences between genders in MOD suggest that men rather develop a right heart phenotype and die from HFpEF, whereas women are more likely to die with HFpEF 29 .