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Background: Heart failure with reduced ejection fraction (HFrEF) remains a significant public health issue, with the disease advancing despite neurohormonal antagonism. Energetic dysfunction is a likely contributor to residual disease progression, and we have previously reported a strong association of plasma metabolite profiles with survival among patients with HFrEF. However, the genetic and biologic mechanisms that underlie the metabolite-survival association in HFrEF were uncertain., Methods and Results: We performed genetic mapping of the key metabolite parameters, followed by mediation analyses of metabolites and genotypes on survival, and genetic pathway analyses. Patients with HFrEF ( n  = 1,003) in the Henry Ford Pharmacogenomic Registry (HFPGR; 500 self-reported Black/African race patients [AA], 503 self-reported White/European race patients [EA], and 249 deaths over a median of 2.7 years) with genome-wide genotyping and targeted metabolomic profiling of plasma were included. We tested genome-wide association (GWA) of single nucleotide polymorphisms (SNPs) with the prognostic metabolite profile (PMP) and its components; first stratified by race, and then combined via meta-analysis for the entire cohort. Seven independent loci were identified as GWA significant hits in AA patients (3 for PMP and 4 for individual metabolites), one of which was also significant in the entire cohort (rs944469). No genome wide significant hits were found in White/EA patients. Among these SNPs, only rs35792152, (a hit for 3.HBA) tended to be associated with mortality in standard survival analysis (HR = 1.436, p  = 0.052). The mediation analyses indicated several significant associations between SNPs, metabolites, and mortality in AA patients. Functional annotation mapping (FUMA) implicated inflammation, DNA metabolic, and mRNA splicing processes., Conclusions: GWAS of key metabolites and survival along with FUMA pathway analysis revealed new candidate genes which unveiled molecular pathways that contribute to HF disease progression via metabolic and energetic abnormalities., Competing Interests: DL has received research funding or support from Akros, Astra Zeneca, Eli Lilly, Pfizer, Illumina, Janssen and SomaLogic, and has acted as consultant to ACI Clinical (Abbott Laboratories), AstraZeneca, Cytokinetics, Duke Clinical Research Institute (CONNECT-HF), Illumina, Janssen, Martin Pharmaceuticals, Ortho Clinical Diagnostics, Otsuka, and ARMGO. HS has received research funding from Novartis, and Impulse Dynamics Inc. and is consultant to Novartis, Impulse Dynamics, Vascular Dynamics, and ViCardia. 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., (© 2024 Revathi Venkateswaran, She, Gui, Luzum, Bryson, Malouf, Williams, Sabbah, Gardell and Lanfear.)

Sexes of a species may show different characteristics beyond the differences in their sexual organs and such sexual dimorphism often occurs in the level of immune response when exposed to pathogens (immunocompetence). In general, females have increased longevity relative to males, which is associated with higher immunocompetence. However, males have higher immunocompetence in some species, such as pipefishes and seahorses. Experimental evidence suggests that this could be because males, rather than females, carry fertilized eggs to birth in these species. This observation suggests that an increase in immunocompetence may be related to the level of parental investment and not to a particular sex. We use state-dependent life-history theory to study optimal investment in offspring production relative to parent immunocompetence, varying the relative time that a parent spends in brooding or pregnancy within a breeding cycle. When offspring is dependent on a parent's survival for a large part of the breeding cycle, we predict higher investments in immunity and longer life expectancies., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Males and females follow distinct life-history strategies that have co-evolved with several sex-specific traits. Higher investment into parental investment (PI) demands an increased lifespan. Thus, resource allocation toward an efficient immune system is mandatory. In contrast, resources allocated toward secondary sexual signals (ornamentation) may negatively correlate with investment into immunity and ultimately result in a shorter lifespan. Previous studies have addressed how resource allocation toward single sex-specific traits impacts lifetime reproductive success (LRS). However, the trade-offs between diverse sex-specific characteristics and their impact on LRS remain largely unassessed impeding our understanding of life-history evolution. We have designed a theoretical framework (informed by experimental data and evolutionary genetics) that explores the effects of multiple sex-specific traits and assessed how they influence LRS. From the individual sex-specific traits, we inferred the consequences at the population level by evaluating adult sex ratios (ASR). Our theory implies that sex-specific resource allocation toward the assessed traits resulted in a biased ASR. Our model focuses on the impact of PI, ornamentation, and immunity as causal to biased ASR. The framework developed herein can be employed to understand the combined impact of diverse sex-specific traits on the LRS and the eventual population dynamics of particular model systems., (© 2021 The Authors. Evolution published by Wiley Periodicals LLC on behalf of The Society for the Study of Evolution.)