Aims To describe the prevalence, overlap, and prognostic implications of physical and social frailties and cognitive dysfunction in hospitalized elderly patients with heart failure. Methods and results The FRAGILE‐HF study was a prospective multicentre cohort study enrolling consecutive hospitalized patients with heart failure aged ≥65 years. The study objectives were to examine the prevalence, overlap, and prognostic implications of the coexistence of multiple frailty domains. Physical frailty, social frailty, and cognitive dysfunction were evaluated by the Fried phenotype model, Makizako's 5 items, and Mini‐Cog, respectively. The primary study outcome was the combined endpoint of heart failure rehospitalization and all‐cause death within 1 year. Among 1180 enrolled hospitalized patients (median age, 81 years; 57.4% male), physical frailty, social frailty, and cognitive dysfunction were identified in 56.1%, 66.4%, and 37.1% of the patients, respectively. The number of identified frailty domains was 0, 1, 2, and 3 in 13.5%, 31.4%, 36.9%, and 18.2% of the patients, respectively. During follow‐up, the combined endpoint occurred in 383 patients. Adjusted hazard ratios for 1, 2, and 3 domains, with 0 domains as the reference, were 1.38 [95% confidence interval (CI) 0.89–2.13; P = 0.15], 1.60 (95% CI 1.04–2.46; P = 0.034), and 2.04 (95% CI 1.28–3.24; P = 0.003), respectively. Incorporating the number of frailty domains into the pre‐existing risk model yielded a 22.0% (95% CI 0.087–0.352; P = 0.001) net reclassification improvement for the primary outcome. Conclusions The coexistence of multiple frailty domains is prevalent in hospitalized elderly patients with heart failure. Holistic assessment of multi‐domain frailty provides additive value to known prognostic factors.
Aims Sarcopenia, one of the extracardiac factors for reduced functional capacity and poor outcome in heart failure (HF), may act differently between HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). We sought to investigate the impact of sarcopenia on mortality in HFpEF and HFrEF. Methods and results We performed a post hoc analysis of a multicentre prospective cohort study, including 942 consecutive older (age ≥65 years) hospitalized patients: 475 with HFpEF (ejection fraction ≥45%, age 81 ± 7 years, 48.8% men) and 467 with HFrEF (ejection fraction <45%, age 78 ± 8 years, 68.1% men). Sarcopenia was diagnosed according to the international criteria incorporating muscle strength (handgrip strength), physical performance (gait speed), and skeletal muscle mass (appendicular skeletal mass). The HFpEF group consisted of fewer patients with low appendicular skeletal muscle mass index measured using bioelectrical impedance analysis [<7.0 kg/m2 (men) and <5.7 (women); 22.1% vs. 31.0%, P = 0.003], and more patients with low handgrip strength [<26 kg (men) and <18 (women); 67.8% vs. 55.5%, P < 0.001], and slow gait speed [<0.8 m/s (both sexes); 54.5% vs. 41.1%, P < 0.001] than the HFrEF group, resulting in a similar sarcopenia prevalence in the two groups (18.1% vs. 21.6%, P = 0.191). Sarcopenia was an independent predictor of 1-year mortality in both HFpEF and HFrEF [hazard ratio (95% confidence interval) 2.42 (1.36–4.32), P = 0.003 in HFpEF and 2.02 (1.08–3.75), P = 0.027 in HFrEF; P for interaction = 0.666] after adjustment for other predictors. Conclusions In older patients with HF, sarcopenia contributes to mortality similarly in HFpEF and HFrEF.
We previously proposed that an endothelin-angiotensin-atrial natriuretic peptide system may contribute to inducing ovulation of mature bovine follicles by modulating follicular secretion of steroids and prostaglandins (PGs). Thus, this study aimed to determine the real-time changes in the local release of angiotensin II (Ang II), endothelin (ET), atrial natriuretic peptide (ANP), PGF(2alpha), and steroid hormones from bovine mature follicles during the periovulatory period in vivo. Seven cows were treated for superovulation using FSH and PGF(2alpha) injections. Two dialysis capillary membranes per follicle were surgically implanted into the theca layer of mature follicles and connected to a microdialysis system (MDS). Fractions of the perfusate were collected from Day -1 (Day 0 = LH surge) to Day 3. Five out of seven treated cows were normally ovulated, and the newly formed corpora lutea were observed at the end of the experiment. In these five ovulated cows, the release of estradiol, androstenedione, and progesterone in the theca layer increased (P < 0.05) synchronously with the LH surge. Acute increases in PGF(2alpha) and Ang II concentrations in the ovarian venous plasma (OVP) were observed at 24-48 h after the peak of the LH surge, when multiple ovulations were expected to occur. The follicular Ang II release was low during the pre-LH surge period and rose (P < 0.05) at the beginning of the increase in the LH surge. On the other hand, ET-1 release dropped (P < 0.05) when plasma LH started to increase. However, no clear changes in ANP concentration in the MDS perfusate and plasma were observed. The above local changes in Ang II, PGF(2alpha), as well as steroid hormones were not observed in cows (n = 2) that did not show an LH surge and ovulation. The present results demonstrate for the first time the local release of Ang II, ET-1, and ANP from the bovine mature follicle in real-time in vivo and show that Ang II and PGF(2alpha) concentrations in the OVP acutely increase around the time of ovulation. The overall results support the concept of a local functional ET-Ang-ANP system in the bovine mature follicle that may be involved in the ovulatory process.
Local regulation of ovulation involves the interaction of LH and intrafollicular factors including steroids, prostaglandins, and peptides derived from endothelial cells, leukocytes, fibroblasts, and steroidogenic cells. To estimate the intrafollicular role of endothelin-1 (ET-1) and its possible interaction with LH, tumor necrosis factor alpha (TNFalpha), and interleukin-1beta (IL-1beta), a microdialysis system was implanted into the theca layer of preovulatory bovine follicles that were maintained in organ culture chambers. The effects of LH, ET-1, TNFalpha, and IL-1beta on the local release of steroids, prostaglandin E2 (PGE2), and ET-1 from the cells surrounding the implanted capillary membrane were investigated. Each preovulatory follicle (selected based on the concentrations of steroids and PGE2) was dissected from surrounding stromal tissue and implanted with 4 capillary dialysis membranes (control, LH, cytokines or ET-1, and LH+cytokine or LH+ET-1) into the theca layer. They were then incubated in organ culture chambers and perfused with Ringer's solution for 14 h after pre-perfusion for 2 h. The stimulation with LH (5 microg/ml) between 4 and 6 h increased the release of progesterone (P4), androstenedione (A), estradiol-17beta (E2), PGE2 (p < 0.001), and ET-1 (p < 0.05). The infusion of ET-1 (250 ng/ml) between 8 and 10 h inhibited P4 and A release but stimulated E2 release (p < 0.05). The infusion of TNFalpha (100 ng/ml) between 8 and 10 h after LH exposure suppressed the release of A and E2 (p < 0.05). IL-1beta (10 ng/ml) between 8 and 10 h stimulated E2 release but inhibited A release (p < 0.05). Moreover, ET-1 and cytokines clearly stimulated PGE2 release (p < 0.05). ET-1 and TNFalpha induced further release of PGE2 stimulated by LH (p < 0. 05). Also, TNFalpha and IL-1beta induced further release of ET-1 stimulated by LH (p < 0.05). These results show that ET-1 is released from the theca layer of mature bovine follicles in vitro and that it affects follicular steroids and PGE2 secretion. The overall results suggest that interactions among ET-1, PGE2, and cytokines may have key roles in a local intermediatory/amplifying system of the LH-triggered ovulatory cascade in the bovine preovulatory follicle.
Recent evidence suggests the presence of a functional endothelin-angiotensin-atrial natriuretic peptide system at the ovarian level. This study aimed to investigate 1) the local interrelationships among angiotensin II (Ang II), endothelin-1 (ET-1), and atrial natriuretic peptide (ANP); 2) the possible effect of each vasoactive peptide on the secretion of steroid hormones and prostaglandins (PGs) in isolated bovine mature follicles; and 3) the expression of mRNAs for Ang II, ET-1, and ANP receptors in the theca layer of follicles at different developmental stages. Each preovulatory follicle obtained before the LH surge (based on the concentrations of steroids and PGs) received implants of 4 capillary dialysis membranes into the theca layer. The follicles were then incubated in organ culture chambers and perfused with Ringer's solution for 12 h. Stimulation by infusion of the different substances into the microdialysis system was carried out between 4 and 8 h. The infusion of ET-1 (10(-7) M) stimulated the release of ANP and estradiol but inhibited the release of androstenedione and progesterone. The infusion of ANP (10(-7) M) stimulated the release of Ang II, progesterone, and androstenedione. Moreover, the infusion of Ang II (10(-5) M) inhibited the release of ANP but stimulated the release of ET-1, progesterone, and estradiol. All three peptides examined increased PGE(2) and PGF(2) release. In the reverse transcription-polymerase chain reaction analysis, expression of the mRNAs for ET type A and type B, and Ang II type 1 receptors did not change with the follicular size and the intrafollicular estradiol concentrations. Expression of the mRNA for the Ang II type 2 receptor dropped in follicles when the estradiol concentration ranged from 20 to 180 ng/ml and increased again when the estradiol concentration was > 180 ng/ml. The levels of expression of ANP type C receptor mRNA were slightly greater in follicles with estradiol concentrations > 20 ng/ml than in follicles with estradiol concentrations < 20 ng/ml. These results demonstrate a complex interaction among Ang II, ET-1, and ANP that may contribute to increasing the follicular production of PGs and modulate steroidogenesis in the bovine mature follicle, thus providing evidence for a local functional endothelin-angiotensin-ANP system.
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