AimsImpaired renal function is associated with worse clinical outcomes in patients with LV systolic dysfunction (LVSD) and heart failure. Renin-angiotensin-aldosterone system (RAAS) inhibitors provide clinical benefit in these settings and often worsen renal function. It is not clear whether worsening renal function (WRF) in patients exposed to these agents predicts a worse prognosis or merely reflects the pharmacological action of the drug on the kidney. Methods and resultsWe performed a meta-analysis of all RAAS inhibitor LVSD trials reporting on outcomes according to WRF (as per individual study definition) in both active intervention and placebo groups. Five major studies (SOLVD, SAVE, RALES, Val-HeFT and EPHESUS) contributed, with 20 573 patients. Compared with placebo, RAAS inhibitors reduced allcause mortality overall [n = 20 573, relative risk ratio (RR) 0.91, 95% confidence interval (CI) 0.86-0.95, P = 0.0003], in the group with no WRF (n = 18 209, RR 0.91, 95% CI 0.83-0.99, P = 0.04), and in the WRF group (n = 2364, RR 0.72, 95% CI 0.62-0.84, P < 0.0001). Compared with no WRF, WRF was associated with increased all-cause mortality; however, this was less in the RAAS inhibitor group (n = 8905, RR 1.22, 95% CI 1.10-1.36, P = 0.0003) than in the placebo group (n = 9304, RR 1.52, 95% CI 1.37-1.69, P < 0.00001).

Testicular tissue cryopreservation can be performed in young patients without delay, preferably prior to cancer treatment. As testicular tissue contains germ cells from which haploid spermatozoa are ultimately derived, future technologies may allow their utilization for fertility in humans. This may be the only hope for biological offspring in some patients undergoing fertility compromising treatment. Retrieval of mature sperm from some pubertal patients, however, offers realistic hope to these patients of future fertility.

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BackgroundAcute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor.Methods and ResultsAdult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in both genotypes; however, this response was significantly blunted in vascular endothelium‐specific ET‐1 knockout mice compared with control mice that were homozygous for the floxed allele. In mice pretreated for 3 days with the endothelin A antagonist, ABT‐627, or the dual endothelin A/B receptor antagonist, A‐182086, the pressor response to CSS was similar between genotypes. CSS significantly increased plasma ET‐1 levels in control mice that were homozygous for the floxed allele. CSS failed to elicit an increase in plasma ET‐1 in vascular endothelium‐specific ET‐1 knockout mice. Telemetry frequency domain analyses suggested similar autonomic responses to stress between genotypes, and isolated resistance arteries demonstrated similar sensitivity to α1‐adrenergic receptor‐mediated vasoconstriction.ConclusionsThese findings specify that acute stress‐induced activation of endothelium‐derived ET‐1 and subsequent endothelin A receptor activation is a novel mediator of the blood pressure response to acute psychosocial stress.

Rate adaptive cardiac pacing (RAP) allows increased heart rate (HR) in response to metabolic demand in people with implantable electronic cardiac devices (IECD). The aim of this work was to conduct a systematic review to determine if RAP increases peak exercise capacity (peak VO2) in line with peak HR in people with chronic heart failure. We conducted a systematic literature search from 1980, when IECD and RAP were first introduced, until 31 July 2021. Databases searched include PubMed, Medline, EMBASE, EBSCO, and the Clinical Trials Register. A comprehensive search of the literature produced a total of 246 possible studies; of these, 14 studies were included. Studies and subsequent analyses were segregated according to comparison, specifically standard RAP (RAPON) vs fixed rate pacing (RAPOFF), and tailored RAP (TLD RAPON) vs standard RAP (RAPON). Pooled analyses were conducted for peak VO2 and peak HR for RAPON vs RAPOFF. Peak HR significantly increased by 15 bpm with RAPON compared to RAPOFF (95%CI, 7.98–21.97, P < 0.0001). There was no significant difference between pacing mode for peak VO2 0.45 ml kg−1 min−1 (95%CI, − 0.55–1.47, P = 0.38). This systematic review revealed RAP increased peak HR in people with CHF; however, there was no concomitant improvement in peak VO2. Rather RAP may provide benefits at submaximal intensities by controlling the rise in HR to optimise cardiac output at lower workloads. HR may be an important outcome of CHF management, reflecting myocardial efficiency.