Female Patients With Sleep-Disordered Breathing Display More Frequently Heart Failure With Preserved Ejection Fraction

Abstract

Objective: Sleep-disordered breathing (SDB) is a widespread disease that is often associated with heart failure (HF) with preserved ejection fraction (HFpEF). HFpEF is more frequent in women than in men, but detailed pathomechanisms remain unclear. We investigated HFpEF in women and men in a high-risk cohort with SDB monitoring. Methods and Results: Three hundred twenty-seven patients (84.4% men) undergoing elective coronary artery bypass grafting were prospectively subjected to SDB monitoring, and an apnea-hypopnea index (AHI) ≥15/h defined SDB. HF was classified according to current guidelines. HFpEF was significantly more frequent in SDB patients compared to those without SDB (28 vs. 17%, P = 0.016). This distribution was driven by an increased frequency of HFpEF in female SDB patients (48% vs. only 25% in male, P = 0.022). In accordance, female patients with SDB exhibited significantly more impaired diastolic left ventricular filling compared to men (echocardiographic E/e'). In contrast to men, in women, minimum oxygen saturation (O2min, measured by polygraphy, R 2 = 0.470, P < 0.001) and time of oxygen saturation <90% (R 2 = 0.165, P = 0.044) were significantly correlated with E/e'. Moreover, the correlation between O2min and E/e' was significantly different in women compared to men (P < 0.001). Intriguingly, this association remained independent of clinical covariates in women [age, body mass index, systolic contractile dysfunction, diabetes mellitus, and glomerular filtration rate (GFR), R 2 = 0.534, P = 0.042, multivariate regression analysis]. Since angiotensin II signaling has been mechanistically linked to HF, we measured protein expression of its cleavage enzyme ACE2 in human right atrial appendage biopsies (Western blot). Intriguingly, we found a significantly decreased ACE2 expression preferentially in women with SDB (2.66 ± 0.42 vs. 4.01 ± 2.47 in men with SDB, P = 0.005). In accordance, left ventricular mass index was significantly increased in women with SDB compared to women without SDB. Conclusion: In patients with SDB, HFpEF and diastolic dysfunction were more frequent in women compared to men. In contrast to men, the severity of SDB was associated with the degree of diastolic dysfunction in women. These insights might help to find sex-specific therapies for patients with sleep-disordered breathing and heart failure. Clinical Trial Registration: Unique identifier: NCT02877745, URL: http://www.clinicaltrials.gov.

Keywords: ACE2; HFpEF; gender; intermittent hypoxia; sex; sleep-disordered breathing.

Conflict of interest statement

MA received consulting fees from ResMed, Philips Respironics, Boehringer-Ingelheim, NRI, Novartis, Bayer, and Bresotec, and grant supports from ResMed as well as ResMed Foundation, all outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Lebek, Hegner, Tafelmeier, Rupprecht, Schmid, Maier, Arzt and Wagner.

Figures

Figure 1

Study flowchart. Study flowchart showing the enrolment of 415 patients undergoing elective coronary artery bypass grafting. After exclusion of 88 patients, 166 patients without SDB and 161 patients with SDB (± right atrial appendage biopsies) were prospectively analyzed.

Figure 2

Increased frequency of HFpEF in women with SDB. (A) Proportion of patients having heart failure with preserved ejection fraction (HFpEF). Interestingly, HFpEF was significantly more common in women with SDB (N = 11/23) compared to men with SDB (N = 34/138). (B) Accordingly, the severity of diastolic dysfunction, estimated by E/e′, was significantly increased in women with SDB (N = 9) compared to women without SDB (N = 16) and men with SDB (N = 50). (C) This resulted in significant correlations between E/e′ with both O2min and time of oxygen saturation <90% (% of total recording time) in women but not in men, indicating that hypoxia may be involved in HFpEF-development in women. (D) Original Western blots for the analysis of ACE2 expression in right atrial appendage biopsies. (E) Intriguingly, densiometric analyses revealed that ACE2 expression was significantly decreased in women with SDB (N = 4), leading to a significant correlation with O2min in women (N = 10) but not in men (N = 82). Statistical comparisons are based on (A) chi-square test (B,E), one-way analysis of variance (ANOVA), and (C,E) linear regression analysis.

Figure 3

Diastolic dysfunction in women with SDB. (A) In accordance with an increased frequency of heart failure in women and men with SDB (Table 1), we observed a significantly increased level of NT-pro BNP in women (N = 19 vs. N = 27) and men (N = 126 vs. N = 119) with SDB. (B) Early diastolic mitral annulus velocity (e′) was significantly decreased in women with SDB (N = 8), indicating diastolic dysfunction. (C) Moreover, left atrial area index was significantly increased in women with SDB (N = 14) compared to women without SDB (N = 15), leading to a significant correlation with O2min in women but not in men. (D) Consistently, we observed a trend toward an increased left atrial volume index in women with SDB (N = 4 vs. N = 6). Statistical comparisons are based on (A,B) Kruskal–Wallis test (C,D) one-way analysis of variance (ANOVA), and (C) linear regression analysis.

Figure 4

Cardiac remodeling in patients with SDB. (A) Left ventricular mass index was significantly increased in women with SDB (N = 8) compared to women without SDB (N = 17). (B) Accordingly, we observed a significantly increased QRS width in women with SDB (N = 18) and a significant correlation with O2min in women (N = 41) (C), proposing that hypoxemia may be especially relevant for myocardial hypertrophy in women. Statistical comparisons are based on (A,B) Kruskal–Wallis test, and (C) linear regression analysis.