Low Circulating Musclin is Associated With Adverse Prognosis in Patients Undergoing Transcatheter Aortic Valve Implantation at Low‐Intermediate Risk

Abstract

Background Musclin is an activity‐stimulated and cardioprotective myokine that attenuates pathological cardiac remodeling. Musclin deficiency, in turn, results in reduced physical endurance. The aim of this study was to assess the prognostic value of circulating musclin as a novel, putative biomarker to identify patients undergoing transcatheter aortic valve implantation (TAVI) who are at a higher risk of death. Methods and Results In this study, we measured systemic musclin levels in 368 patients undergoing TAVI who were at low to intermediate clinical risk (median EuroSCORE [European System for Cardiac Operative Risk Evaluation] II: 3.5; quartile 1–quartile, 2.2%–5.3%), whereby 209 (56.8%) patients were at low and 159 (43.2%) were at intermediate risk. Median preprocedural musclin levels were 2.7 ng/mL (quartile 1–quartile 3, 1.5–4.6 ng/mL). Musclin levels were dichotomized in low (<2.862 ng/mL, n=199 [54.1%]) or high (≥ 2.862 ng/mL, n=169 [45.9%]) groups using cutoff values determined by classification and regression tree analysis. The primary end point was 1‐year overall survival. Patients with low circulating musclin levels exhibited a significantly higher prevalence of frailty, low albumin values, hypertension, and history of stroke as well as higher N‐terminal pro‐B‐type natriuretic peptide. Low musclin levels significantly predicted risk of death in univariable (hazard ratio, 1.81; 95% CI, 1.00–3.53 [ P =0.049]) and multivariable (adjusted hazard ratio, 2.45; 95% CI, 1.06–5.69 [ P =0.037]) Cox regression analyses. Additionally, low musclin levels in combination with conventional EuroSCORE II suggested improved risk stratification in patients undergoing TAVI who were at low to intermediate clinical risk into subgroups with reduced 1‐year survival rates by log‐rank test ( P for trend=0.003). Conclusions Circulating musclin is an independent predictor of 1‐year overall survival in patients undergoing TAVI. Combined with EuroSCORE II, circulating musclin might help to improve prediction of mortality in patients undergoing TAVI who are at low to intermediate clinical risk.

The muscle-enriched myokine Musclin impairs beige fat thermogenesis and systemic energy homeostasis via Tfr1/PKA signaling in male mice

“…More recently, Musclin was shown to function as an exercise-responsive myokine 40 , to attenuate the pathogenesis and progression of several cardiovascular diseases including heart failure during pathological overload 41 , hypertension 42 , cardiac remodeling and congestive heart failure after myocardial infarction 43 , and chronic doxorubicin-induced cardiotoxicity 44 in animal models. In addition, low circulating Musclin levels are associated with adverse prognosis of patients undergoing transcatheter aortic valve implantation (TAVI) 45 , and potential atrial fibrillation in non-diabetic patients 46 . Taken together, these findings demonstrate the tissue-specific and context-dependent roles of Musclin under physiological and pathological conditions.…”

Metabolic remodeling in cardiac hypertrophy and heart failure with reduced ejection fraction occurs independent of transcription factor EB in mice

“…Pathological left ventricular hypertrophy (LVH) and remodeling often cause heart failure (HF) with reduced ejection fraction (HFrEF), which increases morbidity and mortality of affected patients (1). Pathological LVH is an inappropriate response of the heart to various stress stimuli, such as pressure overload (PO) due to aortic valve stenosis or arterial hypertension (2) that is accompanied by cardiomyocyte hypertrophy, interstitial and perivascular fibrosis, and metabolic remodeling (3)(4)(5)(6). At a molecular level, PO leads to an increase in cardiac stress markers, such as atrial natriuretic factor (ANF/ NPPA), B-type natriuretic peptide (BNP/NPPB), and α-skeletal actin (ACTS/ACTA1) as well as a switch from the alpha myosin heavy chain (α-MyHC/MYH6) to the beta MyHC (β-MyHC/ MYH7) isoform (3).…”