Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

Relationship between heart rate recovery and insulin and glucose status in individuals with heart failure – Results from the MyoVasc Study

N. Bélanger1, S. Zeid1, D. Velmeden2, A. Schulz1, T. Koeck1, B. Fooß2, F. Kazemi-Asrar2, F. Müller2, K. J. Lackner3, T. Gori2, T. Münzel4, P. S. Wild1, J. Prochaska2

1Präventive Kardiologie und Medizinische Prävention, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 2Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 3Institut für Klinische Chemie und Laboratoriumsmedizin, Mainz; 4Kardiologie 1, Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz;

Introduction: Autonomic dysfunction (AD) plays a pivotal role in the heart failure (HF) syndrome. Impaired parasympathetic withdrawal, a facet of AD, is represented by heart rate recovery after 60 seconds (HRR60), defined as the decrease in heart rate 1 minute after cessation of peak strain during cardiopulmonary exercise testing (CPET). Metabolic dysregulation was shown to impact both AD and HF. However, the relationships between AD, glucose and insulin status in individuals with HF remain incompletely understood. Methods: Data from the MyoVasc study (NCT04064450; N=3,289), a prospective cohort study on HF, were analyzed. Participants underwent a highly standardized 5-hour examination in a dedicated study center. CPET was performed according to current guidelines' recommendations and used to calculate HRR60. Information on glucose and insulin status was derived from venous blood sampling with subsequent measurement of HbA1c, glucose, insulin, and C-peptide. To assess the individual impact of established glucose and insulin metabolism markers, HbA1c and HOMA-IR, on HRR60, multivariable linear regression models with adjustment for sex, age, traditional cardiovascular risk factors, comorbidities, and medication were calculated. Additional adjustment for complementary glucose or insulin status was performed to analyze the independent relationship between insulin or glucose status and HRR60. C-peptide was investigated as an additional and complementary marker of insulin metabolism. Analyzes were performed in the analysis sample and in clinically relevant subsamples including HF stages and phenotypes. Results: The analysis sample included 1,588 individuals (median age 64.0 years [interquartile range (IQR) 55.0; 72.0]; 33% women) in fasting state. Symptomatic HF stage C/D was present in 43.7% (n=694) of the subjects. Median HRR60 was 21.0 (IQR 14.0; 28.0). In multivariable regression analysis with adjustment for age, sex and clinical profile, both HbA1c (β-estimate per SD -0.074, 95% confidence interval [-0.122; -0.026], p=0.003) and HOMA-IR (βSD -0.113 [-0.165; -0.062], p<0.0001) were predictors of HRR60. Additional adjustment for both glucose and insulin status, respectively, demonstrated that HOMA-IR (βSD -0.097 [-0.155; -0.040], p<0.0001), but not HbA1c (βSD -0.030 [-0.084; 0.025], p=0.28), was independently related to HRR60. This finding was confirmed in individuals with symptomatic HF: HOMA-IR: βSD -0.111 [-0.191; -0.031], p=0.0024; HbA1c: βSD -0.023 [-0.106; 0.06], p=0.59. Sensitivity analysis in HF phenotypes did not reveal clinically relevant differences in glucose and insulin metabolism between HF subjects with reduced (left ventricular ejection fraction (LVEF) ≤50%) and preserved EF (LVEF>50%) (HOMA-IR, p for interaction=0.60 and HbA1c, p for interaction=0.99). In all analyses, C-peptide was related to HRR60 independently of HbA1c with stronger effect size than HOMA-IR (whole sample: βSD -0.171 [-0.225; -0.117], p<0.0001; Stage C/D: βSD -0.173 [-0.245; -0.101], p<0.0001).  Conclusion: The study demonstrates the relevance of insulin status for AD - particularly parasympathetic withdrawal - in individuals with HF. Given the differential impact of insulin and glucose status, the pathophysiological implications merit further mechanistic exploration, especially with regard to the potential for intervention.

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