Exerkines crosstalk muscles, adipose tissua and functionality in patients with advanced heart failure with reduced ejection fraction
M Zaleska-Kociecka, A Paterek, P Blyszczuk, Z W Wojdynska, K Szczesniak, M Mazuruk, M Maczewski, M Nowakowski, H Czerwinska, J Kuriata, K Kusmierski, A Tomaszek, I Michalowska, M Maczewski, P LeszekAbstract
Background
Heart failure with reduced ejection fraction (HFrEF) is characterized by profound alterations in body composition and skeletal muscle dysfunction. Exerkines—exercise-responsive signaling molecules released by muscle, adipose tissue, and other organs—may mediate crosstalk within the adiposity–muscle–function axis, yet their role in advanced HFrEF remains insufficiently defined (1).
Methods
We studied 73 patients with end-stage HFrEF undergoing LVAD implantation and 16 healthy controls. Body composition was assessed by computed tomography, including visceral (VAT), subcutaneous (SAT), and epicardial adipose tissue (EAT) volumes and densities, as well as skeletal muscle quantity (psoas muscle index, PMI) and quality (psoas muscle density, PMD). Functional capacity was evaluated by handgrip strength (HGT) and 6-minute walk test (6MWT). Proteomic profiling was performed using a high-throughput proximity extension assay–based proteomics platform. Age-adjusted linear models with false discovery rate (FDR) correction were applied (Fig.1)
Results
Majority were males (97,2%) with history of dilated cadriomiopathy (56.2%), with mean body mass index (BMI) 28 (SD 4.7) kg/m2. Detailed patient characterisitcs is displayed in Table 1. VAT correlated with muscle mass but not muscle quality or exercise performance. Proteomic profiling revealed a coordinated inflammatory and metabolic stress signature in HFrEF, with elevated CXCL8, CCL2, IL-6, TNF, IL-15, GDF15, FGF21, ANGPTL4, and resistin, and reduced BDNF, IL-7, myostatin, and SPARC. Three biologically coherent signaling axes emerged: (1) a dominant leptin-driven adiposity axis strongly associated with fat volume and density; (2) a muscle quality–associated catabolic axis involving GDF15 and IL-15 inversely related to PMD and functional capacity (6MWT), and myostatin (MSTN)directly propotional to functionality ( 6MWT, HGT), muscle mass (PMI) and its quality PMI while inversly to EAT and VAT density; (3) a neurotrophic–frailty axis characterized by inverse association between BDNF and frailty index.
Conclusions
Advanced HFrEF is characterized by a maladaptive adiposity–muscle–inflammatory signaling network. Exerkine dysregulation links visceral adiposity to impaired muscle quality and functional decline, supporting a systemic cardio–adipose–muscle axis in end-stage heart failure. These findings identify candidate molecular mediators of sarcopenic obesity and functional impairment in HfrEF.Fig.1Patients characteristics