The Role of Muscle Strength and Myosteatosis in the Association of Cardiovascular Risk with Cardiac Function and Remodeling: A 4-Way Decomposition Analysis in the NAKO

Presenting Author(s)

• CS

  Christopher Schuppert, MD

  Attending Physician
  Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  Freiburg, Baden-Wurttemberg, Germany

Primary Author(s)

• CS

  Christopher Schuppert, MD

  Attending Physician
  Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  Freiburg, Baden-Wurttemberg, Germany

Co-Author(s)

• JM

  Juliane Maushagen, MSc

  PhD Student Imaging Epidemiology
  Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, Germany
• TD

  Thierno D. Diallo, MD

  Clinical Researcher
  Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, Germany
• MJ

  Matthias Jung, MD

  Clinical Researcher
  Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, Germany
• MH

  Manuel Hein, MD

  Clinical Researcher
  University Heart Center Freiburg – Bad Krozingen, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, Germany
• JW

  Jakob Weiss, MD

  Clinical Researcher
  Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, Germany
• 

  Jeanette Schulz-Menger, MD

  Head Working Group Cardiac MRI
  Charité/ University Medicine Berlin and Helios
  Berlin, Berlin, Germany
• FB

  Fabian Bamberg, MD, MPH

  Clinical Director
  Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, Germany
• 

  Christopher L. Schlett, MD, MPH

  Deputy Director
  Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  Freiburg, Baden-Wurttemberg, Germany
• SR

  Susanne Rospleszcz, PhD

  Principal Investigator
  Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, Germany

Background: Poor muscle health, including reduced strength, low muscle mass, and myosteatosis, is a well-established predictor of cardiovascular disease (CVD) and mortality in older adults. Its association with subclinical cardiac dysfunction and early remodeling in younger populations, however, is less clear. Because individuals with traditional CVD risk factors often present with poorer muscle health, it may either act synergistically to increase cardiac risk, or represent a step in the causal pathway. This study aimed to clarify the role of muscle health in linking CVD risk factors to cardiac function.

Methods: We analyzed data from participants of the German National Cohort (NAKO) baseline examination who underwent whole-body magnetic resonance imaging (MRI). Cardiac outcomes included the left ventricular global function index (LVGFI) and concentricity. Muscle strength was measured by handgrip strength, and myosteatosis was quantified on MRI as skeletal muscle fat fraction (SMFF, %). Cardiovascular risk factors (diabetes, hypertension, and hypercholesterolemia) were defined using a composite of self-report, medication use, and laboratory values. Mediation and interaction were examined through 4-way decomposition to report total effect (TE), controlled direct effect (CDE), reference interaction (INT_ref), mediated interaction (INT_med), and pure indirect effect (PIE).

Results: The final sample included 21,254 individuals (44% women) with a mean age of 47.7 years. Mean handgrip strength was 49.3 kg in men and 30.6 kg in women, and mean skeletal muscle fat fraction was 16.1% in men and 18.3% in women. Handgrip strength and SMFF were moderately inversely correlated in men (Spearman’s ρ = -0.16) and more strongly in women (ρ = -0.25, Figure 1). Handgrip strength neither interacted with nor mediated the associations of diabetes, hypertension, or hypercholesterolemia with LVGFI or LV concentricity in either sex (Figure 2). In men, however, myosteatosis mediated the associations of all risk factors with LVGFI and of diabetes with LV concentricity, with no evidence of synergistic interaction (Figure 2). For example, for the association of diabetes with LVGFI: TE = -1.77 (-2.31, -1.25), CDE = -1.50 (-2.19, -0.85), INT_ref = -0.03 (-0.24, 0.18), INT_med = -0.03 (-0.20, 0.15), and PIE = -0.21 (-0.28, -0.14). Similarly, in women, myosteatosis mediated the associations of all risk factors with LVGFI and of diabetes and hypertension with LV concentricity, again without evidence of synergistic interaction.

Conclusion: Our findings underscore the critical role of muscle composition in cardiac health. Confirmation of the hypothesized causal pathway will require longitudinal analyses, which will be facilitated by forthcoming data from the NAKO follow-up cohorts.

Figure 1. Correlations of handgrip strength and myosteatosis with MRI-derived measures of cardiac function and remodeling.
Figure 2. Four-way decomposition of the association between hypertension and LVGFI with handgrip strength and myosteatosis as potential mediators. Shown are sex-specific beta coefficients from the 4-way decomposition of effects based on a linear regression model adjusted for age, BMI, diabetes, hypercholesterolemia, physical activity, education, smoking status, and alcohol consumption. TE, total effect; CDE, controlled direct effect; INTref, reference interaction; INTmed, mediated interaction; PIE, pure indirect effect; LVGFI, left ventricular global function index