Belanger N; Department of Cardiology  Gutenberg-University Mainz,  Mainz, Germany.
Zeid S; Velmeden D; Schulz A; Koeck T; Rausch F; Foos B; Kazemi-Asrar F; Lackner KJ;
Gori T; Munzel T; Prochaska JH; Simon P; Wild PS

Cardiovascular Diabetology. 25(1):26, 2026 Jan 08.
VI 1

BACKGROUND: 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.

METHODS: 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 (HbA1c, 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.

RESULTS: 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 HbA1c
([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 HbA1c ([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 HbA1c with higher effect estimates than HOMA-IR
([Formula: see text]per SD -0.171 [- 0.225;-0.117], P < 0.0001). Finally,
higher HbA1c ([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.

CONCLUSIONS: 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.