How does neurohumoral activation correlate with other functional parameters such as cardiac contractility and heart rate variability?

How does neurohumoral activation correlate with other functional parameters such as cardiac contractility and heart rate variability?_6.jpg

Congestive heart failure is characterized not only by decreased pump performance and exercise capacity, but also by neurohumoral activation. Clinical data indicate a relationship between neurohumoral factors and cardiac function, and evidence is accumulating that neurohumoral activation adversely affects survival.

The baroreceptors play a particularly important role in maintaining neurohumoral homeostasis in heart failure. Their sensitivity declines in advanced disease, resulting in excessive sympathetic activation. The reflex response of heart rate, blood pressure, and vascular resistance to carotid occlusion is blunted in dogs with experimental heart failure.

Heart rate variability as a marker of vagal tone, and baroreceptor sensitivity as a marker of the reflex increase in cardiac vagal activity, are increasingly used to assess autonomic regulation in heart failure. Heart rate variability can be analyzed in the time and frequency domain. Simple time domain measures include instantaneous and mean R-R intervals, and day-night differences. The standard deviation of nor-mal-to-normal R-R intervals (SDNN) is the simplest parameter for calculating and reflecting all the components responsible for variability in the chosen time window. In most instances the analysis is performed on 24-hour recordings, although shorter ones can also be used. Spectral analysis displays the magnitude of variability as a function of frequency. In a normal subject during controlled resting conditions, this power spectrum comprises three major frequency (F) components accounting for almost all the signal variability: very low (VLF 0-0.03 Hz), low (LF 0.04-0.15 Hz), and high (HF 0.15-0.45 Hz). This division is not arbitrary, but based on the physiologic interpretation of the components that can be detected in each frequency range. Thus HF, which measures the amplitude of sinus node respiratory arrhythmias, depends mainly on the effects of vagal modulation of the sinus node, whereas LF, particularly when expressed in normalized units, mainly reflects the effects of sympathetic discharge. No conclusive physiologic interpretation of VLF is yet available.

The most widely used method for studying the barore-flex control of heart rate is analysis of the reflex heart rate response to physiologic activation or deactivation of the baroreceptors induced by pharmacologic changes in blood pressure. Angiotensin was initially used as a pressor agent, but has been replaced by phenylephrine, a pure a-adrenoceptor agonist, devoid of direct effects on either cardiac contractility or the central nervous system. Doses of 1 to 4 mg/kg increase systolic blood pressure by 20 to 40 mm Hg over baseline. Given the rapidity of vagal responses, it is assumed that each heart rate period value is related on a cause-and-effect basis to the previous systolic pressure peak, and that this reaction is linear. Prolongations of successive R-R intervals vs baseline are therefore plotted as a function of the preceding systolic pressure changes. The slope of this regression line (expressed in milliseconds of prolonged R-R interval per 1 mm Hg rise in pressure) is used to quantify the sensitivity of the arterial baroreflex control of heart rate. The linearity of the response is tested by calculating the correlation coefficient and its P value; low correlation coefficients with P>0.05 are generally disregarded. A similar linear relationship is obtained when the R-R intervals are shortened by lowering blood pressure with a vasodilator (nitroglycerin or sodium nitroprusside).

Another method of measuring baroreflex sensitivity is the neck chamber technique that allows local activation or deactivation of carotid baroreceptors by applying measurable positive and negative pneumatic pressures to the neck region. The baroreceptors sense an increase in neck chamber pressure as a decrease in arterial pressure, and thus activate a dual response comprising depression of vagal action on the heart and sympathetic stimulation to the arterial vessels. Conversely, a decrease in neck chamber pressure results in reflex reduction of blood pressure and heart rate. Neck suction is easier to use than pressure and it is well tolerated by the subject.

Yoshikawa et al investigated the relationship between cardiac function, neurohumoral factors, and frequency domain variables of heart rate variability and baroreceptor sensitivity in patients with congestive heart failure. Heart rate variability reflected plasma norepinephrine and renin levels, whereas baroreceptor sensitivity independently reflected atrial natriuretic peptide levels. Cardiac function correlated with some neurohumoral factors, but not with heart rate variability’ nor baroreceptor sensitivity. These results confirmed those of an earlier study finding no correlation between heart rate variability measures, left ventricular ejection fraction, cardiac output, or functional classification. Low frequency (LF) power correlated with baroreceptor sensitivity in this study. As markers of autonomic regulation, heart rate variability and baroreceptor sensitivity may be prognostic indicators independent of conventional cardiac function parameters in heart failure.

Braunwald E, Libby P, Zipes DP, et al. Heart Disease: A Textbook of Car Zipes DP, Jalife J, Zorab R. Cardiac Electrophysiology From Cell to Beddiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders; 2001. side. 3rd ed. Philadelphia, Pa: WB Saunders; 2000.

Lombardi F. Heart rate variability: a contribution to a better understanding of the clinical role of heart rate. Eur Heart J. 1999,1 (suppl H):H44-H51.

Yoshikawa T, Baba A, Akaishi M, et al. Neurohumoral activation in congestive heart failure: correlation with cardiac function, heart rate variability and baroreceptor sensitivity. Am Heart J. 1999,137:666-671.


biochemistry; neurohumoral activation; cardiac contractility; heart rate variability; baroreceptor; baroreflex

How does neurohumoral activation correlate with other functional parameters such as cardiac contractility and heart rate variability?_6.jpg

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