Impact of age on clinical outcomes and response to serelaxin in patients with acute heart failure: An analysis from the RELAX-AHF-2 trial.

AIMS: Acute heart failure (AHF) is a major cause of hospitalizations and death in the elderly. However, elderly patients are often underrepresented in randomized clinical trials. We analysed the impact of age on clinical outcomes and response to treatment in patients enrolled in Relaxin in Acute Heart Failure (RELAX-AHF-2), a study that included older patients than in previous AHF trials. METHODS AND RESULTS: The RELAX-AHF-2 randomized patients admitted for AHF to infusion of serelaxin or placebo. We examined the association of pre-specified clinical outcomes and treatment effect according to age categories [(years): <65 (n = 1411), 65-74 (n = 1832), 75-79 (n = 1222), 80-84 (n = 1156) and ≥85 (n = 924)]. The mean age of the 6545 patients enrolled in RELAX-AHF-2 was 73.0 ± 11 years. The risk of all-cause and cardiovascular (CV) death (all p < 0.001) as well as the composite endpoint of CV death or heart failure/renal failure rehospitalization through 180 days (p = 0.002) and hospital discharge through day 60 (p = 0.013) were all directly associated with age categories. Age remained independently associated with outcomes after adjustment for clinical confounders and the results were consistent when age was analysed continuously. No clinically significant change in treatment effects of serelaxin was observed across age categories for the pre-specified endpoints (interaction p > 0.05). CONCLUSION: Elderly patients are at higher risk of short- and long-term CV outcomes after a hospitalization for AHF. Further efforts are needed to improve CV outcomes in this population.

Prediction of the Individual Aortic Stenosis Progression Rate and its Association With Clinical Outcomes.

Background: The progression rate of aortic stenosis differs between patients, complicating clinical follow-up and management. Objectives: This study aimed to identify predictors associated with the progression rate of aortic stenosis. Methods: In this retrospective longitudinal single-center cohort study, all patients with moderate aortic stenosis who presented between December 2011 and December 2022 and had echocardiograms available were included. The individual aortic stenosis progression rate was calculated based on aortic valve area (AVA) from at least 2 echocardiograms performed at least 6 months apart. Baseline factors associated with the progression rate of AVA were determined using linear mixed-effects models, and the association of progression rate with clinical outcomes was evaluated using Cox regression. Results: The study included 540 patients (median age 69 years and 38% female) with 2,937 echocardiograms (median 5 per patient). Patients had a linear progression with a median AVA decrease of 0.09 cm2/y and a median peak jet velocity increase of 0.17 m/s/y. Rapid progression was independently associated with all-cause mortality (HR: 1.77, 95% CI: 1.26-2.48) and aortic valve replacement (HR: 3.44, 95% CI: 2.55-4.64). Older age, greater left ventricular mass index, atrial fibrillation, and chronic kidney disease were associated with a faster decline of AVA. Conclusions: AVA decreases linearly in individual patients, and faster progression is independently associated with higher mortality. Routine clinical and echocardiographic variables accurately predict the individual progression rate and may aid clinicians in determining the optimal follow-up interval for patients with aortic stenosis.

Sex-Specific Transcriptomic Changes in the Villous Tissue of Placentas of Pregnant Women Using a Selective Serotonin Reuptake Inhibitor.

About 5% of pregnant women are treated with selective serotonin reuptake inhibitor (SSRI) antidepressants to treat their depression. SSRIs influence serotonin levels, a key factor in neural embryonic development, and their use during pregnancy has been associated with adverse effects on the developing embryo. However, the role of the placenta in transmitting these negative effects is not well understood. In this study, we aim to elucidate how disturbances in the maternal serotonergic system affect the villous tissue of the placenta by assessing whole transcriptomes in the placentas of women with healthy pregnancies and women with depression and treated with the SSRI fluoxetine during pregnancy. Twelve placentas of the Biology, Affect, Stress, Imaging and Cognition in Pregnancy and the Puerperium (BASIC) project were selected for RNA sequencing to examine differentially expressed genes: six male infants and six female infants, equally distributed over women treated with SSRI and without SSRI treatment. Our results show that more genes in the placenta of male infants show changed expression associated with fluoxetine treatment than in placentas of female infants, stressing the importance of sex-specific analyses. In addition, we identified genes related to extracellular matrix organization to be significantly enriched in placentas of male infants born to women treated with fluoxetine. It remains to be established whether the differentially expressed genes that we found to be associated with SSRI treatment are the result of the SSRI treatment itself, the underlying depression, or a combination of the two.

Subjecting Dams to Early Life Stress and Perinatal Fluoxetine Treatment Differentially Alters Social Behavior in Young and Adult Rat Offspring.

Recently, the putative association between selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy and the development of social disorders in children has gained increased attention. However, clinical studies struggle with the confounding effects of maternal depression typically co-occurring with antidepressant treatment. Furthermore, preclinical studies using an animal model of maternal depression to study effects of perinatal SSRI exposure on offspring social behavior are limited. Therefore, the aim of this study was to investigate effects of perinatal fluoxetine exposure on juvenile and adult social behavior in male and female rat offspring, using an animal model of maternal vulnerability. We exposed heterozygous serotonin transporter (SERT) deficient female rats to early life maternal separation stress, and used this as a model for maternal vulnerability. Control and early life stressed heterozygous serotonin transporter knockout (SERT) dams were treated with the SSRI fluoxetine or vehicle throughout gestation and lactation. Subsequently, both male and female wildtype (SERT+/+) and heterozygous (SERT+/-) rat offspring were tested for pup ultrasonic vocalizations (USVs), juvenile social play behavior and adult social interaction. Fluoxetine treatment of the dams resulted in a reduced total USV duration in pups at postnatal day 6, especially in SERT+/+ males. Perinatal fluoxetine exposure lowered social play behavior in male offspring from both control and early life stressed dams. However, in females a fluoxetine-induced reduction in juvenile play behavior was only present in offspring from control dams. Offspring genotype did not affect juvenile play behavior. Despite fluoxetine-induced behavioral effects at juvenile age, fluoxetine reduced male adult social behavior in offspring from control dams only. Effects of fluoxetine on female adult social behavior were virtually absent. Interestingly, early life stress in dams increased adult social exploration in vehicle exposed SERT+/+ female offspring and total social behavior in fluoxetine exposed adult SERT+/- male offspring. Furthermore, SERT+/- males appeared less social during adulthood compared to SERT+/+ males. Overall, the present study shows that chronic blockade of the serotonin transporter by fluoxetine during early development has a considerable impact on pup USVs, juvenile social play behavior in both male and female offspring, and to a lesser extent on male social interaction in adulthood.