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Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w |
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| Decrypting molecular pathways of insulin metabolism and their impact on heart rate recovery by targeted proteomics - Results from the MyoVasc Study | ||
| N. Bélanger1, S. Zeid1, D. Velmeden2, T. Koeck1, A. Schulz1, B. Fooß2, F. Kazemi-Asrar2, F. Müller2, E. Araldi3, K. J. Lackner4, T. Münzel5, 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; 3Centrum für Thrombose und Hämostase, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 4Institut für Klinische Chemie und Laboratoriumsmedizin, Mainz; 5Kardiologie 1, Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; | ||
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Introduction: Metabolic dysregulation is common in the heart failure (HF) syndrome. A negative impact of insulin metabolism, notably hyperinsulinemia, on heart rate recovery (HRR), reflecting autonomic dysfunction (AD), was found in individuals with HF. However, the underlying molecular pathophysiological mechanisms remain unknown. Methods: Data from the MyoVasc study, a prospective cohort study on HF (NCT04064450; N=3,289), were analyzed. Participants were examined in highly standardized settings including biobanking and cardiopulmonary exercise testing (CPET). A protein signature of HRR 60s after cessation of peak strain during CPET (HRR60) was identified using elastic-net regression and immuno-PCR targeted proteomics (Olink, Uppsala, Sweden). Principal component analysis was applied to determine functional groups and facilitate pathomechanistic and pathway analyses. The predictive value of the principal components (PC) scores for outcome was evaluated using Cox regression. Multivariable linear regressions were utilized for the protein score of each PC with HOMA-IR, C-peptide, and HbA1c as predictors, with adjustment for sex, age, traditional cardiovascular risk factors (CVRFs), comorbidities (including fatty liver disease), and medication. Additional adjustment for complementary glucose or insulin status was performed to analyze the independent relationship between insulin or glucose status and the PC scores.Results: The analysis included 1,588 individuals (median age 64.0 years [interquartile range 55.0; 72.0]; 33% women). The protein signature of HRR60 included 43 proteins and 9 PCs explaining 49.5% of variance of HRR60 were determined. PC1 was the most relevant PC for outcome (all-cause death: Hazard ratio (HR) per SD 1.55, 95% confidence interval (CI) [1.27; 1.88], p<0.0001; worsening of HF: HRSD 1.29 [1.10; 1.51], p=0.0018). C-peptide (β-estimate per SD 0.101, 95% CI [0.039; 0.163], p=0.0015) and HbA1c (βSD 0.136 [0.077; 0.194], p<0.0001) had positive relationships with PC1, which was associated with wound healing and inflammation. Only C-peptide was positively associated with PC2, related to metabolism and extracellular processes (βSD 0.250 [0.192; 0.307], p<0.0001) and negatively associated with cell adhesion (PC3, βSD - 0.114 [-0.180; -0.048], p=0.0008). HOMA-IR (β SD 0.158 [0.104; 0.213], p<0.0001) and C-peptide (βSD 0.266 [0.213; 0.319], p<0.0001) had a positive relationship with processes related to hemostasis and metabolism (PC5) independently of sex, age, CVRFs, comorbidities, medication, and HbA1c. HbA1c was also positively associated with PC5 (βSD 0.092 [0.042; 0.143], p=0.0004) independently of HOMA-IR. HbA1c was negatively associated with LDL oxidation (PC6, βSD -0.142 [-0.204; -0.079], p<0.0001) and redox, proteolysis and immune process (PC9, βSD-0.099 [-0.154; -0.045], p= 0.0004). A differential impact of HOMA-IR (βSD -0.138 [-0.202; -0.074], p<0.0001) and HbA1c (βSD 0.115 [0.056; 0.175], p=0.0002) was observed on processes linked to coagulation, complement and proteolysis (PC7). Conclusion: The study uncovers mechanisms underlying the role of insulin metabolism on AD: vascular damage, and disturbance of key pathways, such as the PI3K/AKT pathway, and inflammation. HbA1c was linked to activation of the coagulation and complement system and oxidative stress, pinpointing the complex and differential impact of metabolic dysregulation in patients with HF. |
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https://dgk.org/kongress_programme/jt2023/aP938.html |