Normal and excessive muscle sympathetic nerve activity in heart failure: implications for future trials of therapeutic autonomic modulation

• Published in: European journal of heart failure Vol. 25; no. 2; pp. 201 - 210
• Main Authors: Badrov, Mark B., Keir, Daniel A., Tomlinson, George, Notarius, Catherine F., Millar, Philip J., Kimmerly, Derek S., Shoemaker, J. Kevin, Keys, Evan, Floras, John S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK John Wiley & Sons, Ltd 01.02.2023
• Subjects: Blood Pressure - physiology; Female; Heart Failure; Heart Rate - physiology; Humans; Male; Microneurography; Muscle, Skeletal; Muscles - innervation; Stroke Volume - physiology; Sympathetic Nervous System; Ventricular Function, Left; Heart failure; Sympathetic nervous system; Microneurography
• ISSN: 1388-9842; 1879-0844
• DOI: 10.1002/ejhf.2749

Aims Patients with sympathetic excess are those most likely to benefit from novel interventions targeting the autonomic nervous system. To inform such personalized therapy, we identified determinants of augmented muscle sympathetic nerve activity (MSNA) in heart failure, versus healthy controls. Methods and results We compared data acquired in 177 conventionally‐treated, stable non‐diabetic patients in sinus rhythm, aged 18–79 years (149 males; 28 females; left ventricular ejection fraction [LVEF] 25 ± 11% [mean ± standard deviation]; range 5–60%), and, concurrently, under similar conditions, in 658 healthy, normotensive volunteers (398 males; aged 18–81 years). In heart failure, MSNA ranged between 7 and 90 bursts·min−1, proportionate to heart rate (p < 0.0001) and body mass index (BMI) (p = 0.03), but was unrelated to age, blood pressure, or drug therapy. Mean MSNA, adjusted for age, sex, BMI, and heart rate, was greater in heart failure (+14.2 bursts·min−1; 95% confidence interval [CI] 12.1–16.3; p < 0.0001), but lower in women (−5.0 bursts·min−1; 95% CI 3.4–6.6; p < 0.0001). With spline modeling, LVEF accounted for 9.8% of MSNA variance; MSNA related inversely to LVEF below an inflection point of ∼21% (p < 0.006), but not above. Burst incidence was greater in ischaemic than dilated cardiomyopathy (p = 0.01), and patients with sleep apnoea (p = 0.03). Burst frequency correlated inversely with stroke volume (p < 0.001), cardiac output (p < 0.001), and peak oxygen consumption (p = 0.002), and directly with norepinephrine (p < 0.0001) and peripheral resistance (p < 0.001). Conclusion Burst frequency and incidence exceeded normative values in only ∼53% and ∼33% of patients. Such diversity encourages selective deployment of sympatho‐modulatory therapies. Clinical characteristics can highlight individuals who may benefit from future personalized interventions targeting pathological sympathetic activation. Muscle sympathetic nerve activity (MSNA) ranged from 7 to 90 bursts·min−1. MSNA burst frequency and burst incidence exceeded healthy normative values in ∼53% and ∼33%, respectively, of treated heart failure (HF) patients. Phenotypes associated with elevated MSNA that could be applied pragmatically in future trials of sympatho‐inhibitory interventions were: male sex; left ventricular ejection fraction (LVEF) <21%; high heart rate (HR) and norepinephrine; low stroke volume (SV) and cardiac output (CO); ischaemic cardiomyopathy; exercise intolerance; and co‐existing sleep apnoea.