M. Esler

Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure.

Although heart rate variability (HRV) at 0.1 Hz has been proposed as a noninvasive clinical measure of cardiac sympathetic nerve firing, this premise has not been sufficiently validated by comparison with techniques such as microneurography and the measurement of norepinephrine spillover from the heart that more directly reflect presynaptic sympathetic activity. Methods and ResultsWe compared the three techniques under conditions of effective cardiac sympathetic denervation, pure autonomic failure (n=4), dopamine β-hydroxylase deficiency (n= 1), and after cardiac transplantation (n=9) as well as in the context of sympathetic nervous activation in cardiac failure (n= 15) and with aging (n= 10). Age-matched comparisons were made in each case with healthy individuals drawn from a pool of 52 volunteers. In pure autonomic failure and early after transplantation, cardiac norepinephrine spillover was negligible, and HRV was low. Late after transplantation, however, cardiac norepinephrine spillover returned to normal levels, and HRV remained low. In comparison to younger subjects (18 to 35 years old), older individuals (60 to 75 years old) had higher muscle sympathetic nerve activity (young, 22.9±1.9; old, 31.3±5.8 bursts per minute; P < .05) and cardiac norepinephrine spillover (young, 14.3±2.5; old, 20.1±3.0 ng/min; P < .05). In contrast, total HRV was reduced by 89%, and at 0.1 Hz it was reduced by 93% (P < .05). Cardiac failure was also characterized by elevated cardiac norepinephrine spillover (cardiac failure patients, 59±4; healthy volunteers, 18±3 ng/min; P < .01) but reduced 0.1 Hz HRV (cardiac failure patients, 49±17; healthy volunteers, 243±4 ms2; P < .05). ConclusionsHRV at 0.1 Hz depends on factors in addition to cardiac sympathetic nerve firing rates, including multiple neural reflexes, cardiac adrenergic receptor sensitivity, postsynaptic signal transduction, and electrochemical coupling, and is not directly related to cardiac norepinephrine spillover, which is a more direct measure of the sympathetic nerve firing rate.

The effects of changes in physical activity on major cardiovascular risk factors, hemodynamics, sympathetic function, and glucose utilization in man: a controlled study of four levels of activity.

The effects of four levels of activity on heart rate, blood pressure, cardiac index, total peripheral resistance index (TPRI), norepinephrine (NE) spillover rate, insulin sensitivity, and levels of lipids and some hormones were studied in 12 normal subjects. The randomized periods were (1) 4 weeks of below-sedentary activity, (2) 4 weeks of sedentary activity, (3) 4 weeks of 40 min of bicycling three times per week, and (4) 4 weeks of similar bicycling seven times per week. Exercise three times per week reduced resting blood pressure by 10/7 mm Hg (p less than .01) and it was reduced by 12/7 mm Hg after exercise seven times per week (both p less than .01). This was associated with reduction in TPRI, an increase in cardiac index, and cardiac slowing. At the highest level of activity, NE spillover rate, an index of sympathetic activity, fell to 35% of the sedentary value (p less than .001) in eight of 10 subjects. In two other subjects NE spillover rate rose, although blood pressure and TPRI were reduced. Metabolic changes included lowering of total cholesterol, but high-density lipoprotein level was unchanged. Insulin sensitivity rose by 27% after exercise three times per week, but declined to sedentary levels with seven times per week exercise. Maximum oxygen uptake increased linearly with activity. Exercise performed three times per week lowers blood pressure and should reduce cardiovascular risk. The same exercise seven times per week enhances physical performance with little further reduction in cardiovascular risk factors. Exercise is potentially a major nonpharmacologic method of lowering blood pressure.

Simultaneous measurements of cardiac noradrenaline spillover and sympathetic outflow to skeletal muscle in humans.

1. Muscle sympathetic nerve activity (MSA) was recorded in the peroneal nerve at the knee by microneurography in ten healthy subjects and determinations were made simultaneously of intra‐arterial blood pressure, and whole‐body and cardiac noradrenaline spillover to plasma. Measurements were made at rest, during isometric handgrip at 30% of maximum power and during stress induced by forced mental arithmetic. 2. At rest there were significant positive correlations between spontaneous MSA (expressed as number of sympathetic bursts min‐1) and both spillover of noradrenaline from the heart and concentration of noradrenaline in coronary sinus venous plasma. 3. Both isometric handgrip and mental arithmetic led to sustained increases of blood pressure, heart rate and MSA. Plasma concentrations of noradrenaline and spillover of noradrenaline (total body and cardiac) increased. In general the effects were more pronounced during handgrip than during stress. 4. When comparing effects during handgrip and stress the ratio between the fractional increases of MSA and cardiac noradrenaline spillover were significantly greater during handgrip. 5. The data suggest (a) that there are proportional interindividual differences in the strength of resting sympathetic activity to heart and skeletal muscle which are determined by a common mechanism and (b) that handgrip and mental stress are associated with differences in balance between sympathetic outflows to heart and skeletal muscle.

Cardiac sympathetic nervous activity in congestive heart failure. Evidence for increased neuronal norepinephrine release and preserved neuronal uptake.

BackgroundIncreased concentrations of norepinephrine in coronary sinus plasma reported in congestive heart failure (CHF) could result from increased cardiac sympathetic nerve firing and norepinephrine release or from failure of neuronal uptake mechanisms to recapture released norepinephrine. We have applied neurochemical indexes of cardiac sympathetic nerve function in heart failure patients to delineate the underlying neural pathophysiology. Methods and ResultsCardiac norepinephrine synthesis, assessed from the cardiac overflow of the norepinephrine precursor dihydroxyphenylalanine (DOPA), intraneuronal metabolism estimated from the overflow of the intraneuronal metabolite dihydroxyphenylglycol (DHPG), neuronal norepinephrine reuptake assessed from the fractional extraction of plasma-tritiated norepinephrine and production of tritiated DHPG across the heart, and norepinephrine spillover to plasma were examined in eight patients with CHF caused by coronary artery disease (left ventricular ejection fraction of 26±5%, meantSEM) and 14 age-matched healthy subjects. Cardiac norepinephrine spillover was increased eightfold in CHF subjects (127 ng/min versus 14 ng/min in healthy subjects; standard error of the difference [SED], 8 ng/min; P<.002), and cardiac DOPA was increased twofold (P<.02). The fractional extraction of tritiated norepinephrine across the heart was marginally less in CHF subjects (0.63 versus 0.73 in normal subjects; SED, 0.02), but the extent to which pharmacological neuronal uptake blockade with desipramine reduced the cardiac extraction of tritiated norepinephrine (by 71% versus 73% in normal subjects) and reduced the production of tritiated DHPG derived from uptake and intraneuronal metabolism of tritiated norepinephrine was similar in CHF patients and healthy subjects. ConclusionsThe marked increase in norepinephrine spillover from the heart in CHF attributable to coronary artery disease results primarily from an increase in sympathetic nerve firing and neuronal release of norepinephrine, not from faulty neuronal reuptake of norepinephrine.

Norepinephrine kinetics in essential hypertension. Defective neuronal uptake of norepinephrine in some patients.

SUMMARY To assess sympathetic nervous system function in essential hypertension, we measured tbe rates of release to and removal from plasma of the sympathetic neurorransmltter, norepinephrine. In normal subjects, disappearance of tritiated /-norepinephrlne from plasma, after infusion to steady state, was biexponential, with

Renal noradrenaline spillover correlates with muscle sympathetic activity in humans.

= 2.0 ± 0.4 minutes (mean ± standard deviation) and

Hydrocortisone-induced hypertension in humans: pressor responsiveness and sympathetic function.

= 33 ± 15 minutes. Tbe rapid component of removal seemed to represent neuronal uptake of norepinephrine: the