Ian T. Meredith

Evidence of a Selective Increase in Cardiac Sympathetic Activity in Patients with Sustained Ventricular Arrhythmias

BACKGROUND Although enhanced efferent cardiac sympathetic nervous activity has been proposed as an important factor in the genesis of ventricular arrhythmias and sudden cardiac death, direct clinical evidence has been lacking. METHODS We measured the rates of total and cardiac norepinephrine spillover into the plasma, which reflect respectively overall and cardiac sympathetic nervous activity, in 12 patients who had recovered from a spontaneous, sustained episode of ventricular tachycardia or ventricular fibrillation outside the hospital 4 to 48 days earlier. The results were compared with those from three age-matched reference groups without a history of ventricular arrhythmias: 12 patients with coronary artery disease, 6 patients with chest pain but normal coronary arteries, and 12 healthy, normal subjects. RESULTS The patients who had had ventricular arrhythmias had reduced left ventricular ejection fractions, as compared with the patients with coronary artery disease or chest pain (mean [+/- SE], 46 +/- 3 percent vs. 58 +/- 4 percent and 69 +/- 5 percent, respectively; P less than 0.003). The rates of total norepinephrine spillover into the plasma were similar in the three reference groups, but 80 percent higher in the patients with ventricular arrhythmias (P less than 0.005). The rate of cardiac norepinephrine spillover was 450 percent higher in these patients (176 +/- 39 pmol per minute, as compared with 32 +/- 8 pmol per minute in the normal subjects; P less than 0.001), a disproportionate increase relative to the increase in total spillover, which indicated selective activation of the cardiac sympathetic outflow. This increase in cardiac norepinephrine spillover was probably caused by a reduction in left ventricular function. CONCLUSIONS These results suggest that in some patients major ventricular arrhythmias are associated with and perhaps caused by sustained and selective cardiac sympathetic activation. We speculate that depressed ventricular function was present before the ventricular arrhythmia occurred, and that this resulted in reflex cardiac sympathetic activation, which in turn contributed to the genesis of the arrhythmia.

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.

Exercise training lowers resting renal but not cardiac sympathetic activity in humans.

Endurance exercise training has previously been shown to reduce the plasma concentration of norepinephrine. Whether reduction in sympathetic activity is responsible for the blood pressure-lowering effects of exercise training is unknown. Using a radiotracer technique, we measured resting total, cardiac, and renal norepinephrine spillover to plasma in eight habitually sedentary healthy normotensive men (aged 36±3 years, mean±SEM) after 1 month of regular exercise and 1 month of sedentary activity, performed in a randomized order. One month of bicycle exercise 3 times/wk (40 minutes at 60-70% maximum work capacity) reduced resting blood pressure by 8/5 mm Hg (p < 0.01) and increased maximum oxygen consumption by 15% (p < 0.05). The fall in blood pressure was attributable to a 12.1% increase in total peripheral conductance. Total norepinephrine spillover to plasma was reduced by 24% from a mean of 438.8 ng/min (p<0.05). Renal norepinephrine spillover fell by an average of 41% from 169.4 ng/min with bicycle training (p<0.05), accounting for the majority (66%) of the fall in total norepinephrine spillover. Renal vascular conductance was increased by 10% (p< 0.05), but this constituted only 18% of the increase in total peripheral conductance. There was no change in cardiac norepinephrine spillover. The reduction in resting sympathetic activity with regular endurance exercise is largely confined to the kidney. The magnitude of the fall in renal vascular resistance, however, is insufficient to directly account for the blood pressure-lowering effect of exercise, although other effects of inhibition of the renal sympathetic outflow may be important

Time-course of the antihypertensive and autonomic effects of regular endurance exercise in human subjects.

To assess the role of different factors on the long-term antihypertensive effect of regular exercise we examined the time course of changes in haemodynamics, oxygen consumption and plasma noradrenaline in 10 normal healthy subjects. For 12 weeks, subjects performed alternating months of training and detraining in a random order. Training involved 40 min of bicycle exercise three times per week at 60-70% of maximum work. Steady-state changes at the end of 1 months exercise were: (1) falls in resting blood pressure when supine and erect by 8/5 and 10/6 mmHg, respectively (P less than 0.01); (2) a reduction in the total peripheral resistance index of 14%; (3) an increase in maximum oxygen consumption of 14% (P less than 0.005); and (4) a fall in plasma noradrenaline of 21% (P less than 0.05). A significant fall in blood pressure occurred at the third training bout (P less than 0.005), at the beginning of the second week, and no further reduction occurred beyond the fourth bout of exercise. The reduction in plasma noradrenaline concentration was confined to the second half of the month in which exercise took place and lagged behind the blood pressure changes. There were significant differences between the rates of the initial fall of blood pressure and noradrenaline, and the times taken for the maximum changes to occur (P less than 0.05). During detraining, blood pressure remained low for 1-2 weeks after cessation of exercise, as did plasma noradrenaline. Both then rose gradually towards the initial sedentary levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Region-Specific Neuropeptide Y Overflows at Rest and During Sympathetic Activation in Humans

Neuropeptide Y coexists with norepinephrine in sympathetic nerves and is coreleased into the circulation on sympathetic activation. Little is known about the regional release of neuropeptide Y in humans under normal conditions or in pathophysiological situations of sympathetic activation or denervation. We measured plasma neuropeptide Y-like immunoreactivity and norepinephrine concentrations in samples taken from the brachial artery; coronary sinus; and internal jugular, antecubital, or hepatic veins in volunteers aged 20 to 64 years. Regional neuropeptide Y overflow at rest was calculated from venoarterial plasma concentration differences and plasma flow, and norepinephrine spillover was determined by [3H]norepinephrine infusion techniques. Cardiac release of neuropeptide Y and norepinephrine was examined in response to various stressors as well as in clinical models of sympathetic activation, cardiac failure, and denervation after cardiac transplantation. In healthy volunteers, cardiac, forearm, and jugular venous sample neuropeptide Y concentrations were similar to arterial levels. Hepatic vein plasma neuropeptide Y was greater than arterial both at rest (119 +/- 5% of arterial, n = 7) and after a meal (132 +/- 12%, n = 7), with neuropeptide Y overflows of 6 +/- 2 and 11 +/- 2 pmol/min, respectively. In contrast, hepatomesenteric norepinephrine spillover was not significantly increased by feeding. Although coronary sinus plasma norepinephrine concentrations increased significantly with the cardiac sympathetic activation accompanying mental arithmetic, coffee drinking, isotonic exercise, and bicycle exercise, only the latter powerful sympathetic stimulus increased neuropeptide Y overflow. Cardiac failure was associated with increased resting release of both norepinephrine and neuropeptide Y from the heart, whereas postcardiac transplant norepinephrine spillover from the heart was reduced. The net overflow of neuropeptide Y to plasma observed at rest across the hepatic circulation, but not the cardiac, forearm, or cerebral circulations, indicates that the gut, the liver, or both make a major contribution to systemic plasma neuropeptide Y levels in humans. Sympathetic activation by exercise produced a modest increase in cardiac neuropeptide Y overflow but to only approximately 25% of the resting input from the gut and without a change in arterial neuropeptide Y concentration. Plasma neuropeptide Y measurements are less sensitive than those of plasma norepinephrine concentrations as an index for quantifying sympathetic neural responses regulating the systemic circulation.

Evidence for increased renal norepinephrine overflow during sodium restriction in humans.

To investigate the differentiated pattern of efferent sympathetic nerve activity by means of analyzing norepinephrine kinetics in response to sodium restriction, cardiorenal sympathetic activity during rest and mental stress was studied in 12 subjects (33.3 +/- 2.6 years old, SEM) exposed to a low and a normal sodium diet; 5-40 mmol and 160-200 mmol/24 hours, respectively (crossover design). Organ norepinephrine release was calculated from organ plasma flow, arteriovenous plasma concentration gradient across the organ and the organs fractional extraction of radiolabeled norepinephrine. Body weight and urinary sodium/24 hr fell significantly and urinary potassium/24 hr and both supine and standing blood pressure remained unchanged. Total norepinephrine release to plasma and norepinephrine plasma clearance were similar in both phases (approximately 460 ng/min and 1.90 l/min, respectively). A 138% increase in renal norepinephrine overflow was observed during sodium restriction (from 112 to 267 ng/min, p less than 0.025), which was due to elevated renal vein norepinephrine (434 versus 290 pg/ml, p less than 0.01) because renal plasma flow and renal norepinephrine extraction were unaltered. Similarly, sodium restriction caused a 168% elevation of renal renin secretion (p less than 0.05). Resting cardiac norepinephrine spillover and cardiac norepinephrine reuptake were unchanged between the two salt phases. Total and cardiac norepinephrine release, supine blood pressure, and heart rate increased to about the same extent in response to mental testing regardless of salt phase. In conclusion, sodium restriction induced a differential and physiological increase in resting renal sympathetic nervous activity, leaving cardiac norepinephrine overflow unchanged. Cardiac norepinephrine uptake was normal, which further supports the concept of a true increase of efferent renal nerve activity.

Biochemical evidence of sympathetic denervation of the heart in pure autonomic failure

Primary autonomic failure is a heterogenous group of diseases with evidence for lesions in both the central and peripheral elements of the autonomic nervous system. We determined the extent of peripheral sympathetic dysfunction in six patients with primary autonomic failure without clinical evidence of central nervous system involvement (pure autonomic failure) using biochemical methods for studying regional noradrenaline spillover and removal. The results were compared with those from 14 agematched normal subjects, seven of whom were studied before and after pharmacological neuronal uptakeblockade with desipramine. Total, cardiac and renal noradrenaline spillover to plasma were 78%, 98% and 66% lower respectively in pure autonomic failure than in normal subjects (p < 0.001). Total noradrenaline plasma clearance was 20% lower in pure autonomic failure (p < 0.005) than in normal subjects and similar to the level observed in normal subjects following neuronal noradrenaline uptake-blockade with desipramine, mean transcardiac extraction of tritiated noradrenaline was 74% in normal subjects and 20% in pure autonomic failure, identical to the value post-desipramine in normal subjects. Cardiac spillover of the noradrenaline precursor, dihydroxyphenylalanine, and the primary intra-neuronal metabolite dihydroxyphenylglycol, were 78% and 94% lower respectively in pure autonomic failure than in normal subjects (p < 0.001). These data indicate a marked reduction in the apparent release rate and neuronal uptake of noradrenaline in the hearts of patients with pure autonomic failure, and provide biochemical evidence of almost total postganglionic sympathetic denervation in this condition.

What is the Dose-Response Relationship between Exercise Training and Blood Pressure?

Most studies of exercise and blood pressure have used a standard exercise programme with a single level of physical activity. To determine the nature of the dose-response relationship however it is necessary to examine several levels of activity, preferably in the same subjects. We have recently performed several randomised crossover studies comparing different levels of regular exercise. The intensity and duration of exercise bouts were constant throughout the studies, but their frequency was varied. Standard bouts consisted of 30 min of bicycling at 60%-70% of maximum work capacity. The exercise was performed either three-weekly or 7-weekly in randomised order and each level was maintained for one month. In sedentary normal subjects three bouts of exercise/week for a total of 90 min lowered blood pressure by 10/7 mmHg. With seven bouts, i.e. a total of 210 min exercise/week, blood pressure was only slightly lower than 3-week exercise and was 12/7 mmHg below sedentary values. Responses to measures of physical fitness including maximum oxygen consumption and work capacity were linearly related to the amount of exercise performed each week. Similar results were obtained in hypertensives. Another randomised study was performed amongst expeditioners to Antarctica where environmental conditions determined that they were sedentary in winter and active in summer. The addition of either 3-week or 7-week exercise in winter significantly lowered blood pressure. In summer when the background level of activity was higher, blood pressure with no added exercise was similar to exercising levels in winter. There was no further fall in blood pressure with either 3-week or 7-week additional exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Is adrenaline released by sympathetic nerves in man

Radiotracer methods were used to measure the rates of regional release of adrenaline and noradrenaline into plasma in man. This was done as a partial test of a theory of essential hypertension pathogenesis which envisages an important cotransmitter function for neuronally released adrenaline. In healthy resting men no release of adrenaline could be detected from the heart, lungs or liver. Adrenaline was released into the right renal vein but an adrenal medullary source is suspected. With the relatively limited activation of the cardiac sympathetic outflow which accompanied mental challenge and isometric exercise, cardiac adrenaline release remained undetectable. During supine bicycle exercise, which increased cardiac noradrenaline release 10–30 fold, to a mean value of 197ng/min, cardiac adrenaline release averaged 2.36 ng/min. In two clinical conditions associated with persistently elevated plasma adrenaline concentrations, cardiac failure and adrenaline-secreting phaeochromocytoma, regional release of adrenaline was clearly evident. Thus, in normal man during exercise, and in patients with cardiac failure at rest, adrenaline is released from non-adrenal sources, and probably from sympathetic nerves. Whether neuronal adrenaline release of the degree found would be sufficient to facilitate noradrenaline release, augment sympathetically-mediated cardiovascular responses and contribute to the development of arterial hypertension remains to be tested.

Effects of exercise and other nonpharmacological measures on blood pressure and cardiac hypertrophy

Reversal of left ventricular hypertrophy (LVH) is an important target of antihypertensive therapy. Nonpharmacological approaches such as weight reduction and exercise training have favorable effects on other risk factors. However, there are few data on their effects on LVH. Athletes have eccentric rather than concentric LVH. A 12-month exercise program in 13 unmedicated hypertensive subjects altered LV geometry, reducing LV wall thickness and increasing LV internal diameters (LVID). LV mass was unchanged, and the thickness/radius fell by 9%. Shorter-term studies have shown that the cardiac structural changes with a moderate exercise program occur rapidly and their onset lags only about 2 weeks behind blood pressure (BP) effects. Assessment of weight loss effects on LVH is complicated by the strong relationship between body weight and ventricular wall thickness. LVID, and LV mass. To some extent, this can be overcome by arbitrarily indexing to body surface area or height. The wall thickness/radius ratio is not related to body size. Weight reduction reduces BP and thickness/radius by 10% in controlled trials. Small studies have also reported reduction in LV mass after sodium restriction in hypertensive subjects. Studies with other nonpharmacological measures could make a substantial contribution to knowledge of their efficacy.