The Intersection of Metabolism and Autonomic Control
For decades, heart failure (HF) has been understood primarily through the lens of hemodynamics and neurohormonal activation. However, contemporary research is increasingly highlighting the systemic nature of the syndrome, particularly the profound interplay between metabolic dysregulation and the autonomic nervous system (ANS). Cardiac autonomic dysfunction, characterized by sympathetic overactivity and a withdrawal of parasympathetic (vagal) tone, is a cornerstone of heart failure progression and a powerful predictor of mortality. While the link between diabetes and cardiovascular disease is well-established, the specific impact of insulin metabolism on the vagal component of the ANS has remained somewhat elusive.
The Myovasc study (NCT04064450) provides a significant leap forward in our understanding of this relationship. By examining a large, prospective cohort of individuals across the heart failure spectrum, researchers have identified that insulin resistance, rather than just chronic hyperglycemia, serves as a primary driver of cardiac vagal impairment. This finding has profound implications for how clinicians approach metabolic management in patients with or at risk for heart failure.
Highlights
- Insulin resistance (HOMA-IR) and C-peptide are independent predictors of impaired heart rate recovery (HRR60), a key marker of vagal activity.
- Glycemic control (HbA1c) loses its independent predictive value for vagal activity once insulin status is accounted for in the model.
- The association between hyperinsulinemia and reduced vagal tone persists in longitudinal analysis over a two-year period.
- C-peptide emerged as a stronger metabolic marker for autonomic dysfunction than the HOMA-IR index.
Background: The Vagal Deficit in Heart Failure
The parasympathetic nervous system acts as the body’s primary braking system for the heart. In healthy individuals, the vagus nerve facilitates a rapid decrease in heart rate following physical exertion. In heart failure, this ‘vagal reactivation’ is often blunted. This deficit is not merely a symptom of a weak heart; it is a pathophysiological state that promotes inflammation, increases myocardial oxygen demand, and predisposes patients to lethal arrhythmias.
Metabolic health is inextricably linked to this process. Conditions such as Type 2 Diabetes (T2D) and Metabolic Syndrome are known to exacerbate autonomic decline. However, the clinical question has always been: is it the high glucose levels (hyperglycemia) or the underlying insulin resistance (hyperinsulinemia) that does the most damage to the vagus nerve? By isolating these variables, the Myovasc study sought to clarify the metabolic architecture of autonomic failure.
Study Design: The Myovasc Cohort
The Myovasc study is a prospective, observational heart failure cohort study designed to investigate the clinical and molecular phenotypes of the disease. For this specific analysis, 1,588 participants were evaluated (median age 64 years; 33% women). The study population was diverse, with 43.7% of subjects exhibiting symptomatic heart failure and a broad spectrum of glucose metabolism dysfunction.
Participants underwent a highly standardized 5-hour clinical examination. The primary endpoint for autonomic function was Heart Rate Recovery at 60 seconds (HRR60) following a maximal cardiopulmonary exercise test (CPET). HRR60 is widely recognized as a reliable non-invasive surrogate for cardiac vagal reactivation. The researchers utilized three primary metabolic markers:
1. HbA1c
A measure of average blood glucose levels over the preceding 2–3 months.
2. HOMA-IR
The Homeostatic Model Assessment for Insulin Resistance, calculated from fasting glucose and insulin.
3. C-peptide
A byproduct of insulin production that serves as a stable marker of endogenous insulin secretion.
Multivariable linear regression models were employed to adjust for age, sex, cardiovascular risk factors, comorbidities, and medications, ensuring that the observed effects were specifically linked to metabolic status.
Key Findings: Decoupling Glucose from Insulin Sensitivity
The results of the Myovasc study offer a nuanced view of the metabolic-autonomic axis. In the initial unadjusted models, both HbA1c and HOMA-IR were significantly associated with lower HRR60. However, the true insight came from the multivariable adjustment.
When HbA1c and HOMA-IR were included in the same model, HOMA-IR remained a robust and independent predictor of impaired vagal reactivation (P < 0.0001), while the significance of HbA1c vanished (P = 0.28). This suggests that the relationship between chronic hyperglycemia and autonomic dysfunction is largely mediated by insulin resistance. In other words, it is the body's inability to handle insulin effectively—and the resulting high levels of circulating insulin—that correlates most strongly with a sluggish vagal response.
This finding held true even in subgroups of patients who already had established Type 2 Diabetes or symptomatic heart failure. It underscores the fact that even in patients where glucose is 'controlled' (as measured by HbA1c), underlying insulin resistance may continue to degrade autonomic health.
The Superiority of C-Peptide
One of the most striking results was the performance of C-peptide as a biomarker. C-peptide was related to HRR60 independently of HbA1c and showed higher effect estimates than the HOMA-IR index (per SD -0.171, P < 0.0001).
Why is C-peptide such a potent marker in this context? Unlike insulin, which has a short half-life and is subject to significant hepatic clearance, C-peptide is more stable and provides a more accurate reflection of the total insulin burden the body is producing. The study suggests that chronic exposure to high levels of endogenous insulin (hyperinsulinemia) may be directly toxic to the autonomic pathways or may reflect a level of systemic inflammation that specifically targets the vagus nerve.
Longitudinal Implications: A Two-Year Perspective
The Myovasc study did not stop at cross-sectional data. The researchers followed participants over a two-year period to observe the trajectory of autonomic function. They found that higher baseline levels of HbA1c and C-peptide were predictive of a lower HRR60 at the two-year mark. This longitudinal evidence reinforces the hypothesis that metabolic dysfunction is a progressive driver of autonomic decline, rather than just a transient correlation.
Expert Commentary: Mechanistic Insights
The pathophysiological link between insulin and the vagus nerve is likely multifactorial. From a mechanistic standpoint, several pathways are plausible. First, insulin resistance is associated with increased oxidative stress and the production of advanced glycation end-products (AGEs), which can cause direct structural damage to peripheral nerve fibers, including the vagus.
Second, hyperinsulinemia has been shown to cross the blood-brain barrier and act on the hypothalamus and the brainstem. In healthy states, insulin can actually stimulate vagal activity; however, in the state of central insulin resistance, this signaling pathway may be subverted, leading to a net reduction in parasympathetic output.
Third, the role of systemic inflammation cannot be ignored. Insulin resistance often goes hand-in-hand with chronic low-grade inflammation, which is known to impair baroreflex sensitivity and vagal tone. The Myovasc findings suggest that the cardiac vagal activity is particularly sensitive to these metabolic disturbances, especially within the vulnerable environment of heart failure.
Clinical Implications and Future Directions
For the practicing clinician, these findings suggest a shift in focus. While maintaining target HbA1c levels remains vital for preventing microvascular complications, it may not be sufficient to preserve cardiac autonomic health. Interventions that specifically target insulin sensitivity—such as weight loss, structured exercise, and certain pharmacological agents like SGLT2 inhibitors or GLP-1 receptor agonists—may offer superior benefits for autonomic preservation.
Furthermore, the study highlights C-peptide as a potentially underutilized tool in risk stratification. If C-peptide is a more reliable indicator of autonomic risk than HbA1c, its inclusion in routine metabolic workups for heart failure patients could help identify those at the highest risk for sudden cardiac death or rapid disease progression.
Conclusion
The Myovasc study provides clear evidence that insulin metabolism is a primary determinant of cardiac vagal activity in heart failure. By demonstrating that insulin resistance and C-peptide levels are independent predictors of impaired heart rate recovery, the research shifts the focus from simple glucose control to the broader challenge of metabolic health. As we move toward a more personalized approach to heart failure management, addressing the ‘metabolic-autonomic axis’ will be essential for improving patient outcomes and slowing the progression of this debilitating syndrome.
Funding and ClinicalTrials.gov
This research was supported by the MyoVasc study framework and various regional health grants. The study is registered at ClinicalTrials.gov under the identifier NCT04064450.
References
1. Bélanger N, Zeid S, Velmeden D, et al. Cardiac vagal activity is associated with insulin metabolism in heart failure: Results from the Myovasc study. Cardiovasc Diabetol. 2026;25(1):26. doi:10.1186/s12933-025-03040-9.
2. Lanza GA, et al. The role of the autonomic nervous system in heart failure. Review of Clinical Evidence. 2023.
3. Freeman R. Autonomic Neuropathy and the Cardiovascular System. Diabetes Care. 2022.
4. Schwartz PJ, et al. Vagus nerve stimulation for the treatment of heart failure. JACC: Heart Failure. 2021.
