Cardiac vagal activity is associated with insulin metabolism in heart failure: Results from the Myovasc study

Cardiac autonomic dysfunction plays a pivotal role in the heart failure syndrome. Metabolic dysregulation affects both autonomic function and heart failure, but these relationships remain incompletely understood. This study aimed at investigating the role of glucose and insulin metabolism for parasympathetic reactivation.

Data from the MyoVasc study (NCT04064450), a prospective heart failure cohort study, were analyzed. Participants underwent a highly standardized 5-hour examination, including venous blood sampling. To assess the impact of glucose and insulin metabolism (HbA_1c, HOMA-IR, and C-peptide) on parasympathetic reactivation as reflected by heart rate recovery 60 s (HRR₆₀) after cardiopulmonary exercise testing, multivariable linear regression models with adjustment for sex, age, clinical profile (cardiovascular risk factors and comorbidities) and medication were calculated in cross-sectional and longitudinal settings. Additional adjustment for complementary glucose or insulin status was performed to assess the dependency of each other. Analyses were carried out in symptomatic heart failure and across the spectrum of glucose metabolism dysfunction.

The analysis sample included 1,588 individuals (median age 64.0 years [IQR 55.0;72.0]; 33% women) in a fasting state. Symptomatic heart failure was present in 43.7% of the subjects. Median HRR₆₀ was 21.0 beats per minute (IQR 14.0;28.0). In multivariable regression analysis with adjustment for age, sex, clinical profile, and medication, both HbA_1c ([Formula: see text]_{per SD} -0.074, 95% CI [- 0.122;-0.026], P = 0.003) and HOMA-IR ([Formula: see text]_{per SD} -0.113 [- 0.165;-0.062], P < 0.0001) predicted HRR₆₀. Additional adjustment for both glucose and insulin status, respectively, demonstrated that HOMA-IR ([Formula: see text]_{per SD} -0.097 [- 0.155;-0.040], P < 0.0001), but not HbA_1c ([Formula: see text]_{per SD} -0.030 [- 0.084;0.025], P = 0.28), was independently related to HRR₆₀. This finding was confirmed in subgroups with heart failure and type 2 diabetes. In all analyses, C-peptide was related to HRR₆₀ independently of HbA_1c with higher effect estimates than HOMA-IR ([Formula: see text]_{per SD} -0.171 [- 0.225;-0.117], P < 0.0001). Finally, higher HbA_1c ([Formula: see text]_{per SD} -0.094, [- 0.171;-0.017], P = 0.017) and C-peptide ([Formula: see text]_{per SD} -0.076, [- 0.159;0.007], P = 0.075) were more strongly associated with a lower HRR₆₀ after two years of follow-up.

This study demonstrates the relevance of insulin status for vagal activity of cardiac autonomic function, particularly in heart failure. The pathophysiological implications underlying the relationship between insulin status and parasympathetic activity merit further mechanistic exploration.