Factors Influencing Muscle Sympathetic Nerve Activity in Human Heart Failure

In heart failure (HF), the magnitude of sympathetic activation predicts both disease progression and mortality. Elevated cardiac norepinephrine (NE) spillover is the earliest documented perturbation, followed later by augmented renal NE spillover and muscle sympathetic nerve activity (MSNA). To date, there is limited understanding of the mechanism(s) responsible for between‐patient variation in MSNA and cohorts studied have been small. To characterize the magnitude of MSNA discharge in HF, its inter‐patient variance, and its principal determinants, we assembled microneurographic data from 177 HF patients (28 females; 53±13 yr; LVEF: 25±11%, range 5‐60%) studied in our laboratory. Data from 658 non‐medicated, normotensive volunteers (CTRL; 260 females; 53±14 yr) acquired contemporaneously under similar conditions served as a reference group. We analyzed, at rest, fibular MSNA, blood pressure (BP), heart rate (HR), LVEF, and etiology of disease, and in a sub‐group (n=63), echocardiographically‐derived stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR). In HF, there was marked inter‐patient variance in MSNA, with burst frequency (BF) ranging from 7 to 90 bursts/minandburst incidence (BI) from 9 to 100 bursts/100 heartbeats. BF was similar in patients dispensed or not dispensed each of the three principal classes of prevailing HF therapy (all P>0.05). BF related directly (R 2 =0.17), and BI inversely (R 2 =0.09), to HR (all P<0.001); neither correlated with BP. For each kg/m 2 rise in BMI, BF increased, on average, by 0.20 bursts/min (95% CI, 0.02‐0.37; P=0.03); its relation to BI was less pronounced (P=0.05). BF increased non‐linearly when LVEF fell below ~21% (P<0.01); above this inflection point, BF displayed no relationship with LVEF. Overall, LVEF accounted for only 9.8% of the variance in BF (P=0.001), while no relationship existed between LVEF and BI (R 2 =0.007). BI (P=0.01), but not BF (P=0.14), was greater in patients with ischemic vs. dilated cardiomyopathy. BF and BI exhibited non‐linear, inverse relationships with SV (R 2 =0.31 and 0.12; all P<0.01) and CO (R 2 =0.17 and 0.20; all P<0.01), and a non‐linear, direct relationship with TPR (R 2 =0.18 and 0.21; all P<0.01). Unadjusted BF (52±15 vs. 26±13 bursts/min; P<0.001) was elevated in HF vs. CTRL. With age, BF exhibited little or no change in HF, in contrast to its non‐linear increase in CTRL. BF, adjusted for age, sex, BMI, and HR, was significantly greater throughout the lifespan (estimate 14.20 bursts/min; 95% CI, 12.11‐16.28; P<0.001) in HF, relative to CTRL, and higher in men than in women (estimate 5.01 bursts/min; 95% CI, 3.42‐6.61; P<0.001). Overall, the extent of sympathetic excess in HF, relative to CTRL, diminished with age. In conclusion, resting MSNA in HF is a function of etiology, BMI, HR, LVEF and SV, but not age; these relationships are significant but moderate to weak, as is that between sympathetic vasoconstrictor discharge and TPR. These observations provide insight into the complexity and individual specificity of mechanisms eliciting muscle sympathetic excitation in human HF.

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