Relationship Between Cardiac Autonomic Markers and Degree of Cardiac Reinnervation in Heart Transplant Patients: Insights from a Mathematical Model

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<h3>Purpose</h3> Cardiac sympathovagal balance is often assessed using autonomic markers derived from cardiac rhythm, however, their relationship to the degree of reinnervation after heart transplantation is still not fully understood. This study aimed to investigate the influence of various levels of vagal and sympathetic cardiac reinnervation on the respective autonomic cardiac markers using a mathematical model of the human cardiovascular system. <h3>Methods</h3> The model integrates chronotropic and inotropic effects of arterial baroreflex and pulmonary stretch reflex, known as main contributors to heart rate variability. The markers of interest included resting heart rate, bradycardic and tachycardic heart rate response to Valsalva maneuver, root mean square error of normalized RR-intervals (RMSDD), high-frequency (HF) power, low-frequency (LF) power, and total power of the heart rate variability spectrum. To analyze how well different levels of sympathetic or vagal cardiac reinnervation can be discriminated through cardiac autonomic markers, five groups of increasing reinnervation levels were formed. The strength of the relationship between the level of cardiac reinnervation was quantified by Spearman's correlation coefficients. <h3>Results</h3> The results suggest that for assessment of vagal cardiac reinnervation levels <20%, resting heart rate (ρ=0.99, p<0.05), RMSDD (ρ=0.97, p<0.05), and total spectral power (ρ=0.89, p<0.05) may be equally suitable as the commonly used measure of HF-power (ρ=0.88, p<0.05). To assess sympathetic reinnervation, our results suggest that LF/HF-ratio (ρ=0.88, p<0.05) and tachycardic response to Valsalva maneuver (ρ=0.84, p<0.05) may be more suitable than LF-power (ρ=0.82, p<0.05). <h3>Conclusion</h3> Our model reports, for the first time, mechanistic relationships between cardiac autonomic markers and degrees of vagal/sympathetic reinnervation. The results suggest differences in the performance of cardiac autonomic markers to assess vagal and sympathetic reinnervation. Although our analysis is purely theoretical yet, the developed mathematical model can provide important insights into the genesis of autonomic cardiac markers and their relationship to cardiac reinnervation and provide indications for clinical study evaluation. This work is funded by the EU-Project NeuHeart (824071).