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Aims: Recently, dipeptidyl peptidase 3 (DPP3) has been discovered as the peptidase responsible for cleavage of angiotensin (1–7) [Ang (1–7)]. Ang (1–7) is part of the angiotensin‐converting enzyme–Ang (1–7)–Mas pathway which is considered to antagonize the renin–angiotensin–aldosterone system (RAAS). Since DPP3 inhibits the counteracting pathway of the RAAS, we hypothesize that DPP3 might be deleterious in the setting of heart failure. However, no data are available on DPP3 in chronic heart failure. We therefore investigated the clinical characteristics and outcome related to elevated DPP3 concentrations in patients with worsening heart failure. Methods and results: Dipeptidyl peptidase 3 was measured in 2156 serum samples of patients with worsening heart failure using luminometric immunoassay (DPP3‐LIA) by 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany. Predictors of DPP3 levels were selected using multiple linear regression with stepwise backward selection. Median DPP3 concentration was 11.45 ng/mL with a range from 2.8 to 84.9 ng/mL. Patients with higher DPP3 concentrations had higher renin [78.3 (interquartile range, IQR 26.3–227.7) vs. 120.7 IU/mL (IQR 34.74–338.9), P < 0.001, for Q1–3 vs. Q4] and aldosterone [88 (IQR 44–179) vs. 116 IU/mL (IQR 46–241), P < 0.001, for Q1–3 vs. Q4] concentrations. The strongest independent predictors for higher concentration of DPP3 were log‐alanine aminotransferase, log‐total bilirubin, the absence of diabetes, higher osteopontin, fibroblast growth factor‐23 and N‐terminal pro‐B‐type natriuretic peptide concentrations (all P < 0.001). In univariable survival analysis, DPP3 was associated with mortality and the combined endpoint of death or heart failure hospitalization (P < 0.001 for both). After adjustment for confounders, this association was no longer significant. Conclusions: In patients with worsening heart failure, DPP3 is a marker of more severe disease with higher RAAS activity. It may be deleterious in heart failure by counteracting the Mas receptor pathway. Procizumab, a specific antibody against DPP3, might be a potential future treatment option for patients with heart failure. [ABSTRACT FROM AUTHOR]

Several studies in patients with acromegaly or growth hormone (GH) deficiency suggest a stimulatory effect of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis on the renin-angiotensin-aldosterone system (RAAS). We analyzed the association of serum IGF-I with plasma aldosterone and the aldosterone-to-renin ratio in a large sample from the general population. In addition to serum IGF-I levels, we also considered the IGF-I-to-IGF binding protein (IGFBP)-3 ratio. A total of 1 504 men and 1 566 women aged 25-88 were selected from the first follow-up of the population-based Study of Health in Pomerania. Plasma aldosterone and renin concentrations, as well as serum IGF-I and IGFBP-3 levels were determined with immunoassays. Analyses of variance and linear regression analyses were performed. We found positive associations between serum IGF-I or the IGF-I/IGFBP-3 ratio with plasma aldosterone in women but not in men. Plasma aldosterone levels increased by 2.91 ng/l per IGF-I standard deviation (SD) and by 2.17 ng/l per IGF-I/IGFBP-3 SD. The associations remained significant after exclusion of subjects taking RAAS-altering medication and of subjects with serum IGF-I levels and aldosterone-to-renin ratios outside the reference range. We conclude that, serum IGF-I and the IGF-I/IGFBP-3 ratio are associated with plasma aldosterone levels in women but not in men from the general population. [ABSTRACT FROM AUTHOR]

Progesterone has a high affinity for the mineralocorticoid receptor and is an antagonist of aldosterone. Almost all synthetic progestogens are devoid of an antimineralocorticoid effect, and are unable to antagonize the salt-retaining effect of estrogens. This property could be one cause of the weight gain and increase in blood pressure associated with the use of combined oral contraceptives and, in some susceptible women, with postmenopausal hormone replacement therapy (HRT). This review illustrates the results of clinical studies with drospirenone, a new progestogen with antialdosterone activity. In normally menstruating women, 3 mg drospirenone per day, taken from day 5 to day 25 of the cycle, inhibits ovulation. A combination of 3 mg drospirenone with 30 μg ethinylestradiol (Yasmin®, Schering AG, Berlin, Germany) is a highly effective and well-tolerated oral contraceptive, with an overall Pearl Index of 0.57 and an adjusted Pearl Index of 0.09. In addition, this combination leads to mild natriuresis and a slight compensatory activation of the renin–aldosterone system. This effect hasbeen clinically demonstrated: compared with an oral contraceptive containing 30 μg ethinylestradiol and 150 μg levonorgestrel, 30 μg ethinylestradiol/3 mg drospirenone, given over 6 months, led to slight decreases in body weight and blood pressure. For postmenopausal HRT, 2 mg drospirenone was combined with 1 mg 17β-estradiol (Angeliq®, Schering AG, Berlin, Germany) for continuous treatment. To evaluate the endometrial safety of this combination, data were assessed from 520 postmenopausal women receiving 1 mg 17β-estradiol and drospirenone (1, 2 or 3 mg per day) for at least 100 weeks. There were no cases of hyperplasia or carcinoma during the entire study period, and 85–92% of women had an atrophic/inactive endometrium. Data from two studies, with a treatment duration of at least 6 months, demonstrated adecrease in mean systolic blood pressure of 1.8 mmHg and a decrease in mean diastolic blood pressure of 3.8 mmHg, after treatment with 1 mg 17β-estradiol/2 mg drospirenonefor 28 weeks. However, in a subgroup of slightly hypertensive women (initial blood pressure of more than 140/90 mmHg), the mean decrease in systolic bloodpressure after 28 weeks of treatment with 1 mg 17β-estradiol/2 mg drospirenonewas 12.5 mmHg, and the mean decrease in diastolic blood pressure was 9.4 mmHg. Since high blood pressure is a cardiovascular risk factor, the use of drospirenone may exert a beneficial effect in this regard. More prolonged studies need to be performed, in order to demonstrate whether negative cardiovascular end-points can be reduced by the new progestogen. In conclusion, drospirenone is not only a safe option for women using oral contraceptives or HRT, but it may offer new medical benefits, via its antimineralocorticoid and antialdosterone effects and its potential to decrease water retention and blood pressure. [ABSTRACT FROM AUTHOR]