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Neurohumoral activations in congestive heart failure: Correlations with cardiac function, heart rate variability, and baroreceptor sensitivity
Neurohumoral activations in congestive heart failure: Correlations with cardiac function, heart rate variability, and baroreceptor sensitivity Tsutomu Yoshikawa, MD, Akiyasu Baba, MD, Makoto Akaishi, MD, Hideo Mitamura, MD, Satoshi Ogawa, MD, Masahiro Suzuki, MD, Koji Negishi, MD, Tetsuo Takahashi, MD, and Akira Murayama, MD, for the Keio Interhospital Cardiology Study (KICS) Investigators Tokyo, Japan
Background The clinical significance of the determination of heart rate variability and baroreceptor sensitivity relating to cardiac function and neurohumoral factors remains to be established.
Methods and Results We investigated the relation between conventional clinical variables and frequency domain analysis of heart rate variability and baroreceptor sensitivity in 146 patients with heart failure. Cardiac function including left ventricular ejection fraction, left ventricular dimensions, and left atrial size was different by the plasma atrial natriuretic peptide level but not by the norepinephrine level. The total power and low-frequency power were correlated with plasma norepinephrine, whereas baroreceptor sensitivity was correlated with plasma atrial natriuretic peptide. None of the frequency domain variables and baroreceptor sensitivity was correlated with cardiac function. There was a positive correlation between the low-frequency power and baroreceptor sensitivity.
Conclusions Heart rate variability and baroreceptor sensitivity, which reflect autonomic regulation, may be an indicator independent from cardiac function in patients with heart failure. (Am Heart J 1999;137:666-71.)
Congestive heart failure is characterized by neurohumoral activation as well as by decreased pump performance and exercise capacity.Accumulating evidence suggests that neurohumoral activation adversely affects survival in patients with congestive heart failure. Cohn et al1 demonstrated that the plasma norepinephrine level was an independent prognostic factor in patients with congestive heart failure.The results of the CONSENSUS Study2 showed that enalapril was effective in patients with congestive heart failure, especially in those with neurohumoral activation, and the V-HeFT II Study3 demonstrated that enalapril, which prevented progressive increases in the plasma norepinephrine level, prolonged survival better than the combination of hydralazine and isosorbide dinitrate, which increased left ventricular ejection fraction and exercise capacity. The SAVE study4 showed that plasma level of renin, aldosterone, arginine-vasopressin, and atrial natriuretic peptide level were independent predictors of the combined end points of cardiovascular death, the development of severe congestive heart failure, and recurrent
From the Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine; National Saitama Hospital; Yokohama Municipal Hospital; and Urawa Municipal Hospital. Submitted July 29, 1997; accepted June 23, 1998. Reprint requests: Tsutomu Yoshikawa, MD, Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 160-8582. Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/1/92715
infarction after myocardial infarction. However, clinical data have shown that there is some relation between these neurohumoral factors and cardiac function.4-6 These observations prompt us to understand the underlying abnormalities in autonomic regulation more clearly by using another independent parameter. Baroreceptor function plays a key role in the maintenance of homeostasis of neurohumoral regulation, especially in the presence of congestive heart failure.7 Baroreceptor sensitivity is attenuated in patients with advanced congestive heart failure, resulting in an excessive activation of sympathetic nerve activity.8-15 Analysis of heart rate variability is increasingly used to assess autonomic regulation in the presence of congestive heart failure.16-20 However, the relation between these measures and other conventional clinical variables including cardiac function and plasma neurohormones is still ill-defined. Our hypothesis was that baroreceptor sensitivity and heart rate variability reflect neurohumoral factors independently from cardiac function.We therefore investigated the relation between clinical variables, including cardiac function and neurohumoral factors, and frequency domain variables of heart rate variability and baroreceptor sensitivity in patients with congestive heart failure.
Methods Study population We enrolled 146 consecutive patients with symptomatic or asymptomatic stable congestive heart failure who had a history of decompensated heart failure. Entry criteria included a left
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ventricular ejection fraction <40% on radionuclide ventriculography or contrast left ventriculography. Exclusion criteria included active myocarditis, alcohol abuse, and other associated severe illness. Ischemic heart disease was defined as the presence of coronary artery stenosis >75% in at least 1 major branch of the 3 coronary arteries or left main trunk on the coronary angiography according to the American Heart Association classification21 or a documented history of myocardial infarction not likely to be related to coronary embolism. Coronary angiography, performed in 95 patients, revealed no significant stenosis in 52 (55%) patients, 1-vessel disease in 20 (21%) patients, 2-vessel disease in 10 (11%) patients, 3-vessel disease in 12 (13%) patients, and involvement of the left main trunk in 1 (1%) patient. Right ventricular endomyocardial biopsies were obtained in 41 patients. Patients were receiving the following medications: digitalis glycosides in 57 (39.0%) patients, diuretics in 105 (71.9%) patients, angiotensin-converting enzyme (ACE) inhibitors in 69 (47.2%) patients, β-blockers in 26 (17.8%) patients, inotropic agents in 9 (6.2%) patients, and antiarrhythmic agents in 32 (21.9%) patients.
Parameters examined Informed consent was obtained in all patients before study. Ultrasonic echocardiography was performed with the use of commercially available equipment and probes. End-diastolic and end-systolic dimensions were determined from M-mode recording. Blood samples for neurohumoral levels were taken after 15-minute bed rest in supine position while the patient’s condition was stable. Plasma catecholamines, renin, aldosterone, arginine-vasopressin, and atrial natriuretic peptide levels were determined. Plasma angiotensin II level was determined in 67 patients who were enrolled in the later phase. We obtained 24-hour ambulatory electrocardiographic recordings that were analyzed with a Marquette system (Marquette,Tokyo, Japan).The frequency domains of heart rate variability were evaluated by spectral analysis in patients with normal sinus rhythm.We determined the total power (0 to 1.0 Hz), the low-frequency power (0.04 to 0.15 Hz), and the high-frequency power (0.15 to 0.40 Hz).The ratio of lowfrequency power to high-frequency power was also calculated to assess sympathetic nerve activity.16 Heart rate variability was examined in the limited patients who were enrolled at the Keio University Hospital and Urawa Municipal Hospital. Baroreceptor sensitivity was determined by the heart rate response to an increase in blood pressure induced by a single bolus injection of 0.04 to 0.20 mg of phenylephrine in patients in sinus rhythm. Blood pressure was continuously and noninvasively measured with the Ohmeda Finapres 2300 NIBP device (Ohmeda Monitoring Systems, Englewood, Colo), which has been found to be highly accurate.22 We previously confirmed that blood pressure measurements obtained by noninvasive methods and direct methods in the presence of phenylephrine-induced vasoconstriction were well correlated.A polyethylene catheter was inserted into an antecubital vein for drug administration, and patients remained in bed in a dark, quiet room for at least 15 minutes before phenylephrine was injected. Patients were unaware of when phenylephrine was injected. Phenylephrine was used to increase blood pressure by ≥20 mm Hg. R-R interval was plotted against the preceding systolic
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Table I. Patient characteristics Age Sex (M/F) NYHA functional class I II III IV Cardiac rhythm (%) Normal sinus rhythm Atrial fibrillation Other Cause of heart failure (%) Primary myocardial disease Ischemic heart disease Valvular heart disease Hypertensive heart disease Other (secondary cardiomyopathy and congenital heart disease) Echocardiography (n = 140) End-diastole (cm) End-systole (cm) Left atrial size (cm) Radionuclide ventriculography (n = 134) Ejection fraction (%) Cardiac catheterization data Pulmonary capillary wedge pressure (n = 103, mm Hg) Cardiac output (n = 102, L/min/m2) End-diastolic volume (n = 81, mL/m2) Ejection fraction (n = 83, %) Neurohumoral factors Plasma norepinephrine (n = 144, pg/mL) Epinephrine (n = 144, pg/mL) Dopamine (n = 144, pg/mL) Renin (n = 144, ng/mL/h) Angiotensin II (n = 67, pg/mL) Aldosterone (n = 144, pg/mL) Arginine-vasopressin (n = 138, pg/mL) Atrial natriuretic peptide (n = 144, pg/mL) Heart rate variability (n = 51) Total power (lnms2) Low-frequency power (lnms2) High-frequency power (lnms2) Low-frequency/high-frequency Baroreceptor sensitivity (n = 30, ms/mm Hg)
59 ± 13 122/24 49 (33.6%) 57 (39.0%) 36 (24.7%) 4 (2.7%) 78.7 17.6 3.7 54.7 37.4 3.6 1.4 2.9 6.3 ± 1.0 5.3 ± 1.0 4.0 ± 0.8 26 ± 9 12 ± 8 3.15 ± 0.85 142 ± 59 31 ± 9 418 ± 285 34 ± 24 17 ± 32 6.7 ± 7.8 21 ± 21 115 ± 105 4.3 ± 7.2 90 ± 83 6.03 ± 1.00 4.47 ± 1.44 3.87 ± 1.13 1.17 ± 0.26 4.33 ± 3.69
In, Natural logainthm of ms2.
blood pressure level, and the slope of the regression line was defined as baroreceptor sensitivity.23 Baroreceptor sensitivity was examined in patients who were enrolled at the Keio University Hospital. Furthermore, diabetic patients were excluded from the analyses of both the heart rate variability and baroreceptor sensitivity. Finally, heart rate variability was evaluated in 51 patients, and baroreceptor sensitivity was determined in 30 patients. Table I shows the baseline characteristics of all study subjects.The mean plasma norepinephrine level was 418 pg/mL. We classified patients into a high norepinephrine group (≥418 pg/mL) and a low norepinephrine group (<418 pg/mL) and compared variables in these groups. Similarly, we classified the study patients into 2 groups according to the plasma atrial natriuretic peptide level, with a mean of 90 pg/mL.
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Table II. Relation between plasma norepinephrine and study variables High Low norepinephrine norepinephrine Age NYHA functional class End-diastolic dimension (mm) End-systolic dimension (mm) Left atrial size (mm) Ejection fraction (%) Epinephrine (pg/mL) Dopamine (pg/mL) Renin (ng/mL/h) Angiotensin II (pg/mL) Aldosterone (pg/mL) Arginine-vasopressin (pg/mL) Atrial natriuretic peptide (pg/mL) Total power (lnms2) Low-frequency power (lnms2) High-frequency power (lnms2) Low-frequency/high-frequency Baroreceptor sensitivity (ms/mm Hg)
63 ± 12 (50) 2.2 ± 0.8 (49) 6.3 ± 1.0 (50) 5.3 ± 1.0 (50) 3.9 ± 0.7 (49) 24 ± 9 (49) 43 ± 27 (53) 24 ± 36 (53) 10.4 ± 9.1 (53) 33 ± 31 (23) 149 ± 137 (53) 7.2 ± 10.9 (49) 107 ± 90 (53) 5.38 ± 0.92 (15) 3.70 ± 1.44 (15) 3.32 ± 1.04 (15) 1.12 ± 0.30 (15) 2.25 ± 2.73 (8)
57 ± 13 (90)* 2.0 ± 0.8 (89) 6.4 ± 1.0 (88) 5.4 ± 1.1 (88) 4.0 ± 0.9 (83) 27 ± 9 (83) 28 ± 20 (91)* 13 ± 29 (91) 4.6 ± 6.1 (91)* 17 ± 11 (44)* 95 ± 74 (91)* 2.6 ± 3.0 (89)* 81 ± 77 (91) 6.30 ± 0.93 (35)* 4.80 ± 1.35 (35)* 4.11 ± 1.11 (35)* 1.18 ± 0.24 (35) 5.15 ± 3.84 (21)
High norepinephrine denotes plasma norepinephrine ≥418 pg/mL; low norepinephrine denotes plasma norepinephrine <418 pg/mL. Numbers in parentheses indicate number of patients. In, Natural logarithm of ms2. *P < .05, high norepinephrine vs low norepinephrine.
Statistical analysis Data are expressed as mean ± SD.The least-squares method was used to determine baroreceptor sensitivity. Differences between groups were assessed by a nonpaired t test.A value of P < .05 was accepted as indicating statistical significance.
Results There was no significant difference in the New York Heart Association (NYHA) functional class between subgroups of patients classified according to the plasma norepinephrine level (Table II).The mean age was higher in the high norepinephrine group than in the low norepinephrine group.The left ventricular end-diastolic and end-systolic dimensions were similar in both groups.There was no difference in ejection fraction between the 2 groups. Plasma levels of epinephrine, renin, angiotensin II, aldosterone, and arginine-vasopressin were significantly higher in the high norepinephrine group, but plasma levels of atrial natriuretic peptide and dopamine were not different between the 2 groups.There was no difference in the use of medications between the 2 groups, including ACE inhibitors (53% vs 49%) and diuretics (78% vs 80%). Spectral analysis of heart rate variability revealed that the total power, low-frequency power, and high-frequency power were lower in the high norepinephrine group than in the low norepinephrine group.There was no difference in the low-frequency/high-frequency power or baroreceptor sensitivity between groups.
Table III shows differences between high versus low atrial natriuretic peptide groups.There was no difference in age between the 2 groups.The NYHA functional class was greater in patients with high than in those with low atrial natriuretic peptide levels.The left ventricular dimensions and left atrial size were larger and ejection fraction was lower in patients with high atrial natriuretic peptide levels.There was no difference in the plasma neurohormones except for norepinephrine, which was significantly higher in the high atrial natriuretic peptide group.There was no difference in the frequency domains of heart rate variability between the 2 groups. However, baroreceptor sensitivity was significantly lower in the high than in the low atrial natriuretic peptide group. The total power and low-frequency power were inversely correlated with plasma norepinephrine level (P = .0068, P = .0170).The total power was also correlated with plasma renin activity (P = .0373). None of the frequency domain variables was correlated with levels of atrial natriuretic peptide or the left ventricular ejection fraction. Low-frequency power was correlated with baroreceptor sensitivity (P = .0408). Baroreceptor sensitivity was inversely correlated with the plasma level of atrial natriuretic peptide (P = .0164) but not with plasma norepinephrine.There was no correlation between ejection fraction and baroreceptor sensitivity, either.Age was not correlated with the frequency domains of heart rate variability, baroreceptor sensitivity, ejection fraction, left ventricular dimensions, and neurohumoral factors, except for plasma norepinephrine (P = .017) and aldosterone (P = .0207). Preliminary data on survival were obtained in 133 (91.1%) patients.Thirteen patients were lost to followup. Mean follow-up period was 19 months, ranging from 1 to 60 months.There were 28 (21.1%) deaths, with cardiac death in 26 and noncardiac death in 2 patients. Plasma norepinephrine, renin, and atrial natriuretic peptide levels were higher in nonsurvivors than in survivors.The left ventricular ejection fraction was lower in nonsurvivors than in survivors. High-frequency power tended to be lower although statistically insignificant in nonsurvivors (Table IV).
Discussion Neurohumoral factors The left ventricular ejection fraction was different by plasma atrial natriuretic peptide level but not by norepinephrine level.The left ventricular dimensions and the left atrial size were also different by plasma atrial natriuretic peptide level. Previous studies have shown a weak relation between cardiac function and neurohumoral factors in patients with moderate congestive heart failure.4,5 Recently, the SOLVD Investigators6 examined the relation between neurohumoral factors
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Table III. Relation between plasma natriuretic peptide and study variables
Age NYHA functional class End-diastolic dimension (cm) End-systolic dimension (cm) Left atrial size (cm) Ejection fraction (%) Norepinephrine (pg/mL) Epinephrine (pg/mL) Dopamine (pg/mL) Renin (ng/mL/h) Angiotensin II (pg/mL) Aldosterone (pg/mL) Arginine-vasopressin (pg/mL) Total power (lnms2) Low-frequency power (lnms2) High-frequency power (lnms2) Low-frequency/high-frequency Baroreceptor sensitivity (ms/mm Hg)
High ANP
Low ANP
61 ± 13 (50) 2.4 ± 0.8 (50) 6.8 ± 1.1 (50) 5.8 ± 1.1 (50) 4.2 ± 1.0 (49) 22 ± 8 (47) 512 ± 355 (50) 34 ± 28 (50) 24 ± 46 (50) 7.4 ± 8.8 (50) 16 ± 10 (20) 115 ± 112 (50) 4.5 ± 7.7 (48) 5.82 ± 0.81 (21) 4.04 ± 1.34 (21) 3.69 ± 0.88 (21) 1.09 ± 0.26 (21) 2.09 ± 2.65 (11)
59 ± 13 (90) 1.9 ± 0.7 (88)* 6.1 ± 0.8 (88)* 5.1 ± 0.9 (88)* 3.8 ± 0.6 (83)* 28 ± 8 (85)* 366 ± 224 (94)* 33 ± 22 (94) 14 ± 20 (94) 6.4 ± 7.3 (94) 25 ± 24 (47) 115 ± 101 (94) 4.2 ± 7.0 (90) 6.18 ± 1.13 (29) 4.78 ± 1.48 (29) 4.01 ± 1.29 (29) 1.22 ± 0.25 (29) 5.72 ± 3.72 (18)*
High ANP denotes plasma atrial natriuretic peptide ≥90 pg/mL; low ANP denotes plasma atrial natriuretic peptide <90 pg/mL. Numbers in parentheses indicate number of patients. In, Natural logarthm of ms2. *P < .05, high ANP vs low ANP.
and clinical variables in 859 patients with congestive heart failure.The left ventricular ejection fraction was weakly correlated with plasma norepinephrine, renin, and arginine-vasopressin levels but strongly correlated with atrial natriuretic peptide level.Atrial natriuretic peptide level was also correlated with left ventricular dimension and left atrial size.These results were consistent with the current study. Plasma epinephrine, renin, angiotensin II, aldosterone, and arginine-vasopressin levels were higher in patients with high norepinephrine levels than in those with low norepinephrine levels.There was no difference in atrial natriuretic peptide levels between high and low norepinephrine groups.The difference in the relations between plasma norepinephrine and atrial natriuretic peptide levels relating to cardiac function and other neurohumoral factors suggests that different regulatory mechanisms are involved in congestive heart failure.
Heart rate variability The total power, low-frequency power, and high-frequency power were significantly lower in patients with high plasma norepinephrine levels than in those with low plasma norepinephrine levels. Parameters of cardiac function, including left ventricular ejection fraction, were not correlated with frequency domain variables.The total power and low-frequency power were correlated with plasma norepinephrine level but not with atrial natriuretic peptide level. Saul et al16 found no clear correlation between specific frequency domain variables and plasma norepinephrine levels in
patients with congestive heart failure. Kingwell et al18 reported that low-frequency oscillations (0.1 Hz) were markedly reduced in patients with congestive heart failure than in age-matched healthy volunteers.There was no correlation between low-frequency oscillations and cardiac norepinephrine spillover, although the cardiac norepinephrine spillover was correlated with muscle sympathetic nerve activity in healthy volunteers. In contrast, Kienzle et al17 reported that power spectral variables of heart rate variability were inversely correlated with plasma norepinephrine level in patients with class II to IV congestive heart failure, although heart rate variability was not correlated with clinical variables, including age, left ventricular ejection fraction, cardiac output, and functional classification.The current study, which excluded patients with diabetes mellitus, clearly showed that the frequency domains of heart rate variability were inversely correlated with plasma norepinephrine level in a larger sample size. Sympathetic nerve activity is altered in the aging heart. Subgroup analysis in the SOLVD study6 revealed age-related increases in plasma norepinephrine and atrial natriuretic peptide levels in patients with congestive heart failure.White et al24 observed significant agerelated decreases in β-adrenergic receptor density, adenylyl cyclase activity, and the level of stimulatory guanine nucleotide protein in nonfailing myocardium from donor hearts. Kingwell et al18 reported that cardiac norepinephrine spillover and muscle sympathetic nerve activity were significantly increased and the frequency domain of heart rate variability decreased in
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Table IV. Differences between survivors and nonsurvivors Survivors Age 59 ± 13 (105) NYHA functional class 2.0 ± 0.8 (105) End-diastolic dimension (cm) 6.4 ± 0.8 (104) End-systolic dimension (cm) 5.3 ± 1.0 (104) Left atrial size (cm) 4.0 ± 0.8 (99) Ejection fraction (%) 27 ± 9 (100) Norepinephrine (pg/mL) 371 ± 242 (104) Epinephrine (pg/mL) 33 ± 23 (104) Dopamine (pg/mL) 15 ± 27 (104) Renin (ng/mL/h) 5.6 ± 7.0 (104) Angiotensin II (pg/mL) 22 ± 24 (49) Aldosterone (pg/mL) 109 ± 88 (104) Arginine-vasopressin (pg/mL) 3.04 ± 4.08 (98) Atrial natriuretic peptide (pg/mL) 84 ± 74 (104) Total power (lnms2) 6.16 ± 1.08 (37) Low-frequency power (lnms2) 4.67 ± 1.55 (37) High-frequency power (lnms2) 4.06 ± 1.19 (37) Low-frequency/high-frequency 1.15 ± 0.26 (37) Baroreceptor sensitivity 4.66 ± 3.68 (22) (ms/mm Hg)
Nonsurvivors 62 ± 13 (28) 2.3 ± 0.9 (28) 6.4 ± 1.4 (28) 5.5 ± 1.3 (27) 4.1 ± 1.0 (27) 23 ± 7 (27)* 581 ± 360 (28)* 34 ± 28 (28) 27 ± 48 (28) 11.0 ± 10.0 (28)* 24 ± 16 (11) 151 ± 157 (28) 5.31 ± 9.08 (28) 132 ± 112 (28)* 5.68 ± 0.61 (11) 3.84 ± 0.95 (11) 3.40 ± 0.79 (11) 1.17 ± 0.29 (11) 2.19 ± 2.98 (6)
Numbers in parentheses indicate number of patients. In, Natural logarithm of ms2. *P < .05 nonsurvivors vs survivors.
older healthy individuals. Saul et all6 observed a significant inverse correlation between age and the frequency domain of heart rate variability in control subjects but not in patients with congestive heart failure.The frequency domain of heart rate variability was lower in patients with high plasma norepinephrine in the current study, but we also observed a significant age-related increase in plasma norepinephrine level.We cannot, therefore, exclude the possibility that age differences were responsible for the decreases in the power of frequency domains. However, there was no correlation between age and frequency domain in the current study, which suggests that the increase in the plasma norepinephrine level per se was related to the alteration in heart rate variability.
Baroreceptor sensitivity It is well known that baroreceptor-mediated control is attenuated in congestive heart failure. In human beings, Sopher et al13 used a ramped neck pressure-suction sequence to unload and stimulate carotid sinus baroreceptors, measuring heart rate at each step to calculate arterial baroreceptor reflex sensitivity.Arterial baroreceptor–heart rate reflex sensitivity was less in patients with heart failure than in normal subjects. Ferguson et al14 examined muscle sympathetic nerve activity during perturbation of blood pressure by using phenylephrine and nitroprusside in patients with moderate to severe congestive heart failure and found that baroreflex response during nitroprusside-induced
baroreceptor deactivation was strikingly attenuated but sympathoinhibitory response to pressor stimulus was not in patients with heart failure. Baroreceptor sensitivity was correlated with plasma atrial natriuretic peptide level but not with plasma norepinephrine.There was a significant correlation between baroreceptor sensitivity and the low-frequency power. There was no correlation between baroreceptor sensitivity and high-frequency power, which reflects parasympathetic nervous activity,25,26 although baroreceptor sensitivity during increase in blood pressure may reflect vagal afferent pathway.27 These results are difficult to interpret. Some studies have suggested that plasma atrial natriuretic peptide level affects baroreceptor sensitivity.28,29 Volpe et al28 found that the increase in baroreceptor sensitivity induced by atrial natriuretic peptide was abolished by administration of an ACE inhibitor.They speculated that the effect of atrial natriuretic peptide was mediated by inhibition of angiotensin II, which affects baroreceptor sensitivity.Woods et al29 found that atrial natriuretic peptide affected baroreceptor sensitivity when assessed by the ramp method but not by the steady-state method and suggested that atrial natriuretic peptide preferentially affects a nonarterial baroreceptor component, such as the cardiopulmonary reflex.The close correlation observed between plasma atrial natriuretic peptide level and baroreceptor sensitivity in the current study supports these findings.An increase in atrial natriuretic peptide may be one of the compensatory mechanisms for the attenuated baroreceptor sensitivity in patients with congestive heart failure. Like the frequency domains of heart rate variability, baroreceptor sensitivity may also be affected by aging.30 Again, there was no correlation between age and baroreceptor sensitivity in the current study.Thus increases in neurohumoral factors appeared to be related to the decrease in baroreceptor sensitivity.The baroreceptor–heart rate sensitivity that we assessed may be affected by a number of other factors, such as nonarterial baroreflex components and end-organ responsiveness.Assessment of the pure carotid sinus baroreflex with the use of a neck chamber or direct recording of sympathetic nerve activity would be needed to exclude the influence of these factors.
Heart rate variability and baroreceptor sensitivity as indexes of autonomic regulation in congestive heart failure In this study, heart rate variability reflected plasma norepinephrine and renin levels, whereas baroreceptor sensitivity independently reflected atrial natriuretic peptide level.Although cardiac function was correlated with some neurohumoral factors, it was not correlated with heart rate variability or baroreceptor sensitivity. These findings are consistent with the results of a previous study, which showed that none of the measures of
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heart rate variability was correlated with left ventricular ejection fraction, cardiac output, or functional classification.17 The low-frequency power was correlated with baroreceptor sensitivity in this study. In this regard, these measures reflecting autonomic regulation independently could be prognostic indicators different from other conventional clinical variables in patients with congestive heart failure. We thank the following investigators who participated in the study: Keiichi Nagami, MD, Keiyu Hospital, Yokohama; Michiyo Hosokawa, MD, and Hitoshi Yokozuka, MD, Urawa Municipal Hospital, Urawa; Tomomi Meguro, MD, Mito Red Cross Hospital, Mito; and Natsuki Kobayashi, MD, Saitama Central Hospital, Urawa.
References 1. Cohn JN, Levine B, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with congestive heart failure. N Engl J Med 1984;311:819-23. 2. The CONSENSUS Trial Study Group. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation 1990;82:1730-6. 3. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-10. 4. SAVE Study Group. Prognostic value of neurohumoral activation in patients with an acute myocardial infarction. J Am Coll Cardiol 1994; 24:583-91. 5. Francis GS, Goldsmith SR, Cohn JN. Relationship of exercise capacity to resting left ventricular performance and basal plasma norepinephrine levels in patients with congestive heart failure. Am Heart J 1982;104:725-31. 6. SOLVD Investigators. Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction. J Am Coll Cardiol 1994;23:1410-20. 7. Packer M. Neurohumoral interactions and adaptations in congestive heart failure. Circulation 1988;77:721-30. 8. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med 1971; 285:877-83. 9. Greenberg TT, Richmond WH, Stocking RA, et al. Impaired atrial receptor responses in dogs with heart failure due to tricuspid insufficiency and pulmonary artery stenosis. Circ Res 1973;32:424-33. 10. Goldstein RE, Beiser GD, Stampfer M, et al. Impairment of autonomically mediated heart rate control in patients with cardiac dysfunction. Circ Res 1975;36:571-8. 11. Zucker IH, Earle AM, Gilmore JP. The mechanism of adaptation of left atrial stretch receptors in dogs with chronic congestive heart failure. J Clin Invest 1977;60:323-31. 12. Ferguson DW, Abboud FM, Mark AL. Selective impairment of baroreflex-mediated vasoconstrictor responses in patients with ventricular dysfunction. Circulation 1984;69:451-60.
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13. Sopher SM, Smith ML, Eckberg DL, et al. Autonomic pathophysiology in heart failure: carotid baroreceptor-cardiac reflexes. Am J Physiol 1990;259:H689-96. 14. Ferguson DW, Berg WJ, Roach PJ, et al. Effects of heart failure on baroreflex control of sympathetic neural activity. Am J Cardiol 1992; 69:523-31. 15. Grassi G, Seravalle G, Cattaneo BM, et al. Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Circulation 1995;92:3206-11. 16. Saul JP, Arai Y, Berger RD, et al. Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis. Am J Cardiol 1988;61:1292-9. 17. Kienzle MG, Ferguson DW, Birkett CL, et al. Clinical, hemodynamic and sympathetic correlates of heart rate variability in congestive heart failure. Am J Cardiol 1992;15:761-7. 18. Kingwell BA, Thompson JM, Kaye DM, et al. Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure. Circulation 1994;90:234-40. 19. Parina G, Khot UN, Nunziata E, et al. Role of spectral measures of heart rate variability as markers of disease progression in patients with chronic congestive heart failure not treated with angiotensinconverting enzyme inhibitors. Am Heart J 1996;131:153-7. 20. Szabo BM, Veldhuisen DJ, van der Veer N, et al. Prognostic value of heart rate variability in chronic congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 1997;79:978-80. 21. Austen WG, Edwards JE, Frye RL, et al. A reporting system on patients evaluated for coronary artery disease. Circulation 1975; 51:5-40. 22. Imholz BPM, Parati G, Mancia G, et al. Effects of graded vasoconstriction upon the measurement of finger arterial pressure. J Hypertens 1992;10:979-84. 23. Smyth HS, Sleight P, Pickering GW. Reflex regulation of arterial pressure during sleep in man. Circ Res 1969;24:109-21. 24. White M, Roden R, Minobe W, et al. Age-related changes in βadrenergic neuroeffector systems in the human heart. Circulation 1994;90:1225-38. 25. Akselrod S, Gordon D, Ubel FA, et al. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 1981;213:220-3. 26. Pomeranz B, Macaulay RJB, Caudill MA, et al. Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 1985;248:H151-3. 27. Creager MA, Creager SJ. Arterial baroreflex regulation of blood pressure in patients with congestive heart failure. J Am Coll Cardiol 1994;23:401-5. 28. Volpe M, Lembo G, Condorelli G, et al. Converting enzyme inhibition prevents the effects of atrial natriuretic factor on baroreflex responses in humans. Circulation 1990;82:1214-21. 29. Woods RL, Courneya C-A, Head GA. Nonuniform enhancement of baroreflex sensitivity by atrial natriuretic peptide in conscious rats and dogs. Am J Physiol 1994;267:H678-86. 30. Parati G, Hrattola A, DiRienzo M, et al. Effects of aging on 24-h dynamic baroreceptor control of heart rate in ambulant subjects. Am J Physiol 1995;268:H1608-12.
Background The clinical significance of the determination of heart rate variability and baroreceptor sensitivity relating to cardiac function and neurohumoral factors remains to be established.
Methods and Results We investigated the relation between conventional clinical variables and frequency domain analysis of heart rate variability and baroreceptor sensitivity in 146 patients with heart failure. Cardiac function including left ventricular ejection fraction, left ventricular dimensions, and left atrial size was different by the plasma atrial natriuretic peptide level but not by the norepinephrine level. The total power and low-frequency power were correlated with plasma norepinephrine, whereas baroreceptor sensitivity was correlated with plasma atrial natriuretic peptide. None of the frequency domain variables and baroreceptor sensitivity was correlated with cardiac function. There was a positive correlation between the low-frequency power and baroreceptor sensitivity.
Conclusions Heart rate variability and baroreceptor sensitivity, which reflect autonomic regulation, may be an indicator independent from cardiac function in patients with heart failure. (Am Heart J 1999;137:666-71.)
Congestive heart failure is characterized by neurohumoral activation as well as by decreased pump performance and exercise capacity.Accumulating evidence suggests that neurohumoral activation adversely affects survival in patients with congestive heart failure. Cohn et al1 demonstrated that the plasma norepinephrine level was an independent prognostic factor in patients with congestive heart failure.The results of the CONSENSUS Study2 showed that enalapril was effective in patients with congestive heart failure, especially in those with neurohumoral activation, and the V-HeFT II Study3 demonstrated that enalapril, which prevented progressive increases in the plasma norepinephrine level, prolonged survival better than the combination of hydralazine and isosorbide dinitrate, which increased left ventricular ejection fraction and exercise capacity. The SAVE study4 showed that plasma level of renin, aldosterone, arginine-vasopressin, and atrial natriuretic peptide level were independent predictors of the combined end points of cardiovascular death, the development of severe congestive heart failure, and recurrent
From the Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine; National Saitama Hospital; Yokohama Municipal Hospital; and Urawa Municipal Hospital. Submitted July 29, 1997; accepted June 23, 1998. Reprint requests: Tsutomu Yoshikawa, MD, Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 160-8582. Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/1/92715
infarction after myocardial infarction. However, clinical data have shown that there is some relation between these neurohumoral factors and cardiac function.4-6 These observations prompt us to understand the underlying abnormalities in autonomic regulation more clearly by using another independent parameter. Baroreceptor function plays a key role in the maintenance of homeostasis of neurohumoral regulation, especially in the presence of congestive heart failure.7 Baroreceptor sensitivity is attenuated in patients with advanced congestive heart failure, resulting in an excessive activation of sympathetic nerve activity.8-15 Analysis of heart rate variability is increasingly used to assess autonomic regulation in the presence of congestive heart failure.16-20 However, the relation between these measures and other conventional clinical variables including cardiac function and plasma neurohormones is still ill-defined. Our hypothesis was that baroreceptor sensitivity and heart rate variability reflect neurohumoral factors independently from cardiac function.We therefore investigated the relation between clinical variables, including cardiac function and neurohumoral factors, and frequency domain variables of heart rate variability and baroreceptor sensitivity in patients with congestive heart failure.
Methods Study population We enrolled 146 consecutive patients with symptomatic or asymptomatic stable congestive heart failure who had a history of decompensated heart failure. Entry criteria included a left
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ventricular ejection fraction <40% on radionuclide ventriculography or contrast left ventriculography. Exclusion criteria included active myocarditis, alcohol abuse, and other associated severe illness. Ischemic heart disease was defined as the presence of coronary artery stenosis >75% in at least 1 major branch of the 3 coronary arteries or left main trunk on the coronary angiography according to the American Heart Association classification21 or a documented history of myocardial infarction not likely to be related to coronary embolism. Coronary angiography, performed in 95 patients, revealed no significant stenosis in 52 (55%) patients, 1-vessel disease in 20 (21%) patients, 2-vessel disease in 10 (11%) patients, 3-vessel disease in 12 (13%) patients, and involvement of the left main trunk in 1 (1%) patient. Right ventricular endomyocardial biopsies were obtained in 41 patients. Patients were receiving the following medications: digitalis glycosides in 57 (39.0%) patients, diuretics in 105 (71.9%) patients, angiotensin-converting enzyme (ACE) inhibitors in 69 (47.2%) patients, β-blockers in 26 (17.8%) patients, inotropic agents in 9 (6.2%) patients, and antiarrhythmic agents in 32 (21.9%) patients.
Parameters examined Informed consent was obtained in all patients before study. Ultrasonic echocardiography was performed with the use of commercially available equipment and probes. End-diastolic and end-systolic dimensions were determined from M-mode recording. Blood samples for neurohumoral levels were taken after 15-minute bed rest in supine position while the patient’s condition was stable. Plasma catecholamines, renin, aldosterone, arginine-vasopressin, and atrial natriuretic peptide levels were determined. Plasma angiotensin II level was determined in 67 patients who were enrolled in the later phase. We obtained 24-hour ambulatory electrocardiographic recordings that were analyzed with a Marquette system (Marquette,Tokyo, Japan).The frequency domains of heart rate variability were evaluated by spectral analysis in patients with normal sinus rhythm.We determined the total power (0 to 1.0 Hz), the low-frequency power (0.04 to 0.15 Hz), and the high-frequency power (0.15 to 0.40 Hz).The ratio of lowfrequency power to high-frequency power was also calculated to assess sympathetic nerve activity.16 Heart rate variability was examined in the limited patients who were enrolled at the Keio University Hospital and Urawa Municipal Hospital. Baroreceptor sensitivity was determined by the heart rate response to an increase in blood pressure induced by a single bolus injection of 0.04 to 0.20 mg of phenylephrine in patients in sinus rhythm. Blood pressure was continuously and noninvasively measured with the Ohmeda Finapres 2300 NIBP device (Ohmeda Monitoring Systems, Englewood, Colo), which has been found to be highly accurate.22 We previously confirmed that blood pressure measurements obtained by noninvasive methods and direct methods in the presence of phenylephrine-induced vasoconstriction were well correlated.A polyethylene catheter was inserted into an antecubital vein for drug administration, and patients remained in bed in a dark, quiet room for at least 15 minutes before phenylephrine was injected. Patients were unaware of when phenylephrine was injected. Phenylephrine was used to increase blood pressure by ≥20 mm Hg. R-R interval was plotted against the preceding systolic
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Table I. Patient characteristics Age Sex (M/F) NYHA functional class I II III IV Cardiac rhythm (%) Normal sinus rhythm Atrial fibrillation Other Cause of heart failure (%) Primary myocardial disease Ischemic heart disease Valvular heart disease Hypertensive heart disease Other (secondary cardiomyopathy and congenital heart disease) Echocardiography (n = 140) End-diastole (cm) End-systole (cm) Left atrial size (cm) Radionuclide ventriculography (n = 134) Ejection fraction (%) Cardiac catheterization data Pulmonary capillary wedge pressure (n = 103, mm Hg) Cardiac output (n = 102, L/min/m2) End-diastolic volume (n = 81, mL/m2) Ejection fraction (n = 83, %) Neurohumoral factors Plasma norepinephrine (n = 144, pg/mL) Epinephrine (n = 144, pg/mL) Dopamine (n = 144, pg/mL) Renin (n = 144, ng/mL/h) Angiotensin II (n = 67, pg/mL) Aldosterone (n = 144, pg/mL) Arginine-vasopressin (n = 138, pg/mL) Atrial natriuretic peptide (n = 144, pg/mL) Heart rate variability (n = 51) Total power (lnms2) Low-frequency power (lnms2) High-frequency power (lnms2) Low-frequency/high-frequency Baroreceptor sensitivity (n = 30, ms/mm Hg)
59 ± 13 122/24 49 (33.6%) 57 (39.0%) 36 (24.7%) 4 (2.7%) 78.7 17.6 3.7 54.7 37.4 3.6 1.4 2.9 6.3 ± 1.0 5.3 ± 1.0 4.0 ± 0.8 26 ± 9 12 ± 8 3.15 ± 0.85 142 ± 59 31 ± 9 418 ± 285 34 ± 24 17 ± 32 6.7 ± 7.8 21 ± 21 115 ± 105 4.3 ± 7.2 90 ± 83 6.03 ± 1.00 4.47 ± 1.44 3.87 ± 1.13 1.17 ± 0.26 4.33 ± 3.69
In, Natural logainthm of ms2.
blood pressure level, and the slope of the regression line was defined as baroreceptor sensitivity.23 Baroreceptor sensitivity was examined in patients who were enrolled at the Keio University Hospital. Furthermore, diabetic patients were excluded from the analyses of both the heart rate variability and baroreceptor sensitivity. Finally, heart rate variability was evaluated in 51 patients, and baroreceptor sensitivity was determined in 30 patients. Table I shows the baseline characteristics of all study subjects.The mean plasma norepinephrine level was 418 pg/mL. We classified patients into a high norepinephrine group (≥418 pg/mL) and a low norepinephrine group (<418 pg/mL) and compared variables in these groups. Similarly, we classified the study patients into 2 groups according to the plasma atrial natriuretic peptide level, with a mean of 90 pg/mL.
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Table II. Relation between plasma norepinephrine and study variables High Low norepinephrine norepinephrine Age NYHA functional class End-diastolic dimension (mm) End-systolic dimension (mm) Left atrial size (mm) Ejection fraction (%) Epinephrine (pg/mL) Dopamine (pg/mL) Renin (ng/mL/h) Angiotensin II (pg/mL) Aldosterone (pg/mL) Arginine-vasopressin (pg/mL) Atrial natriuretic peptide (pg/mL) Total power (lnms2) Low-frequency power (lnms2) High-frequency power (lnms2) Low-frequency/high-frequency Baroreceptor sensitivity (ms/mm Hg)
63 ± 12 (50) 2.2 ± 0.8 (49) 6.3 ± 1.0 (50) 5.3 ± 1.0 (50) 3.9 ± 0.7 (49) 24 ± 9 (49) 43 ± 27 (53) 24 ± 36 (53) 10.4 ± 9.1 (53) 33 ± 31 (23) 149 ± 137 (53) 7.2 ± 10.9 (49) 107 ± 90 (53) 5.38 ± 0.92 (15) 3.70 ± 1.44 (15) 3.32 ± 1.04 (15) 1.12 ± 0.30 (15) 2.25 ± 2.73 (8)
57 ± 13 (90)* 2.0 ± 0.8 (89) 6.4 ± 1.0 (88) 5.4 ± 1.1 (88) 4.0 ± 0.9 (83) 27 ± 9 (83) 28 ± 20 (91)* 13 ± 29 (91) 4.6 ± 6.1 (91)* 17 ± 11 (44)* 95 ± 74 (91)* 2.6 ± 3.0 (89)* 81 ± 77 (91) 6.30 ± 0.93 (35)* 4.80 ± 1.35 (35)* 4.11 ± 1.11 (35)* 1.18 ± 0.24 (35) 5.15 ± 3.84 (21)
High norepinephrine denotes plasma norepinephrine ≥418 pg/mL; low norepinephrine denotes plasma norepinephrine <418 pg/mL. Numbers in parentheses indicate number of patients. In, Natural logarithm of ms2. *P < .05, high norepinephrine vs low norepinephrine.
Statistical analysis Data are expressed as mean ± SD.The least-squares method was used to determine baroreceptor sensitivity. Differences between groups were assessed by a nonpaired t test.A value of P < .05 was accepted as indicating statistical significance.
Results There was no significant difference in the New York Heart Association (NYHA) functional class between subgroups of patients classified according to the plasma norepinephrine level (Table II).The mean age was higher in the high norepinephrine group than in the low norepinephrine group.The left ventricular end-diastolic and end-systolic dimensions were similar in both groups.There was no difference in ejection fraction between the 2 groups. Plasma levels of epinephrine, renin, angiotensin II, aldosterone, and arginine-vasopressin were significantly higher in the high norepinephrine group, but plasma levels of atrial natriuretic peptide and dopamine were not different between the 2 groups.There was no difference in the use of medications between the 2 groups, including ACE inhibitors (53% vs 49%) and diuretics (78% vs 80%). Spectral analysis of heart rate variability revealed that the total power, low-frequency power, and high-frequency power were lower in the high norepinephrine group than in the low norepinephrine group.There was no difference in the low-frequency/high-frequency power or baroreceptor sensitivity between groups.
Table III shows differences between high versus low atrial natriuretic peptide groups.There was no difference in age between the 2 groups.The NYHA functional class was greater in patients with high than in those with low atrial natriuretic peptide levels.The left ventricular dimensions and left atrial size were larger and ejection fraction was lower in patients with high atrial natriuretic peptide levels.There was no difference in the plasma neurohormones except for norepinephrine, which was significantly higher in the high atrial natriuretic peptide group.There was no difference in the frequency domains of heart rate variability between the 2 groups. However, baroreceptor sensitivity was significantly lower in the high than in the low atrial natriuretic peptide group. The total power and low-frequency power were inversely correlated with plasma norepinephrine level (P = .0068, P = .0170).The total power was also correlated with plasma renin activity (P = .0373). None of the frequency domain variables was correlated with levels of atrial natriuretic peptide or the left ventricular ejection fraction. Low-frequency power was correlated with baroreceptor sensitivity (P = .0408). Baroreceptor sensitivity was inversely correlated with the plasma level of atrial natriuretic peptide (P = .0164) but not with plasma norepinephrine.There was no correlation between ejection fraction and baroreceptor sensitivity, either.Age was not correlated with the frequency domains of heart rate variability, baroreceptor sensitivity, ejection fraction, left ventricular dimensions, and neurohumoral factors, except for plasma norepinephrine (P = .017) and aldosterone (P = .0207). Preliminary data on survival were obtained in 133 (91.1%) patients.Thirteen patients were lost to followup. Mean follow-up period was 19 months, ranging from 1 to 60 months.There were 28 (21.1%) deaths, with cardiac death in 26 and noncardiac death in 2 patients. Plasma norepinephrine, renin, and atrial natriuretic peptide levels were higher in nonsurvivors than in survivors.The left ventricular ejection fraction was lower in nonsurvivors than in survivors. High-frequency power tended to be lower although statistically insignificant in nonsurvivors (Table IV).
Discussion Neurohumoral factors The left ventricular ejection fraction was different by plasma atrial natriuretic peptide level but not by norepinephrine level.The left ventricular dimensions and the left atrial size were also different by plasma atrial natriuretic peptide level. Previous studies have shown a weak relation between cardiac function and neurohumoral factors in patients with moderate congestive heart failure.4,5 Recently, the SOLVD Investigators6 examined the relation between neurohumoral factors
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Table III. Relation between plasma natriuretic peptide and study variables
Age NYHA functional class End-diastolic dimension (cm) End-systolic dimension (cm) Left atrial size (cm) Ejection fraction (%) Norepinephrine (pg/mL) Epinephrine (pg/mL) Dopamine (pg/mL) Renin (ng/mL/h) Angiotensin II (pg/mL) Aldosterone (pg/mL) Arginine-vasopressin (pg/mL) Total power (lnms2) Low-frequency power (lnms2) High-frequency power (lnms2) Low-frequency/high-frequency Baroreceptor sensitivity (ms/mm Hg)
High ANP
Low ANP
61 ± 13 (50) 2.4 ± 0.8 (50) 6.8 ± 1.1 (50) 5.8 ± 1.1 (50) 4.2 ± 1.0 (49) 22 ± 8 (47) 512 ± 355 (50) 34 ± 28 (50) 24 ± 46 (50) 7.4 ± 8.8 (50) 16 ± 10 (20) 115 ± 112 (50) 4.5 ± 7.7 (48) 5.82 ± 0.81 (21) 4.04 ± 1.34 (21) 3.69 ± 0.88 (21) 1.09 ± 0.26 (21) 2.09 ± 2.65 (11)
59 ± 13 (90) 1.9 ± 0.7 (88)* 6.1 ± 0.8 (88)* 5.1 ± 0.9 (88)* 3.8 ± 0.6 (83)* 28 ± 8 (85)* 366 ± 224 (94)* 33 ± 22 (94) 14 ± 20 (94) 6.4 ± 7.3 (94) 25 ± 24 (47) 115 ± 101 (94) 4.2 ± 7.0 (90) 6.18 ± 1.13 (29) 4.78 ± 1.48 (29) 4.01 ± 1.29 (29) 1.22 ± 0.25 (29) 5.72 ± 3.72 (18)*
High ANP denotes plasma atrial natriuretic peptide ≥90 pg/mL; low ANP denotes plasma atrial natriuretic peptide <90 pg/mL. Numbers in parentheses indicate number of patients. In, Natural logarthm of ms2. *P < .05, high ANP vs low ANP.
and clinical variables in 859 patients with congestive heart failure.The left ventricular ejection fraction was weakly correlated with plasma norepinephrine, renin, and arginine-vasopressin levels but strongly correlated with atrial natriuretic peptide level.Atrial natriuretic peptide level was also correlated with left ventricular dimension and left atrial size.These results were consistent with the current study. Plasma epinephrine, renin, angiotensin II, aldosterone, and arginine-vasopressin levels were higher in patients with high norepinephrine levels than in those with low norepinephrine levels.There was no difference in atrial natriuretic peptide levels between high and low norepinephrine groups.The difference in the relations between plasma norepinephrine and atrial natriuretic peptide levels relating to cardiac function and other neurohumoral factors suggests that different regulatory mechanisms are involved in congestive heart failure.
Heart rate variability The total power, low-frequency power, and high-frequency power were significantly lower in patients with high plasma norepinephrine levels than in those with low plasma norepinephrine levels. Parameters of cardiac function, including left ventricular ejection fraction, were not correlated with frequency domain variables.The total power and low-frequency power were correlated with plasma norepinephrine level but not with atrial natriuretic peptide level. Saul et al16 found no clear correlation between specific frequency domain variables and plasma norepinephrine levels in
patients with congestive heart failure. Kingwell et al18 reported that low-frequency oscillations (0.1 Hz) were markedly reduced in patients with congestive heart failure than in age-matched healthy volunteers.There was no correlation between low-frequency oscillations and cardiac norepinephrine spillover, although the cardiac norepinephrine spillover was correlated with muscle sympathetic nerve activity in healthy volunteers. In contrast, Kienzle et al17 reported that power spectral variables of heart rate variability were inversely correlated with plasma norepinephrine level in patients with class II to IV congestive heart failure, although heart rate variability was not correlated with clinical variables, including age, left ventricular ejection fraction, cardiac output, and functional classification.The current study, which excluded patients with diabetes mellitus, clearly showed that the frequency domains of heart rate variability were inversely correlated with plasma norepinephrine level in a larger sample size. Sympathetic nerve activity is altered in the aging heart. Subgroup analysis in the SOLVD study6 revealed age-related increases in plasma norepinephrine and atrial natriuretic peptide levels in patients with congestive heart failure.White et al24 observed significant agerelated decreases in β-adrenergic receptor density, adenylyl cyclase activity, and the level of stimulatory guanine nucleotide protein in nonfailing myocardium from donor hearts. Kingwell et al18 reported that cardiac norepinephrine spillover and muscle sympathetic nerve activity were significantly increased and the frequency domain of heart rate variability decreased in
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Table IV. Differences between survivors and nonsurvivors Survivors Age 59 ± 13 (105) NYHA functional class 2.0 ± 0.8 (105) End-diastolic dimension (cm) 6.4 ± 0.8 (104) End-systolic dimension (cm) 5.3 ± 1.0 (104) Left atrial size (cm) 4.0 ± 0.8 (99) Ejection fraction (%) 27 ± 9 (100) Norepinephrine (pg/mL) 371 ± 242 (104) Epinephrine (pg/mL) 33 ± 23 (104) Dopamine (pg/mL) 15 ± 27 (104) Renin (ng/mL/h) 5.6 ± 7.0 (104) Angiotensin II (pg/mL) 22 ± 24 (49) Aldosterone (pg/mL) 109 ± 88 (104) Arginine-vasopressin (pg/mL) 3.04 ± 4.08 (98) Atrial natriuretic peptide (pg/mL) 84 ± 74 (104) Total power (lnms2) 6.16 ± 1.08 (37) Low-frequency power (lnms2) 4.67 ± 1.55 (37) High-frequency power (lnms2) 4.06 ± 1.19 (37) Low-frequency/high-frequency 1.15 ± 0.26 (37) Baroreceptor sensitivity 4.66 ± 3.68 (22) (ms/mm Hg)
Nonsurvivors 62 ± 13 (28) 2.3 ± 0.9 (28) 6.4 ± 1.4 (28) 5.5 ± 1.3 (27) 4.1 ± 1.0 (27) 23 ± 7 (27)* 581 ± 360 (28)* 34 ± 28 (28) 27 ± 48 (28) 11.0 ± 10.0 (28)* 24 ± 16 (11) 151 ± 157 (28) 5.31 ± 9.08 (28) 132 ± 112 (28)* 5.68 ± 0.61 (11) 3.84 ± 0.95 (11) 3.40 ± 0.79 (11) 1.17 ± 0.29 (11) 2.19 ± 2.98 (6)
Numbers in parentheses indicate number of patients. In, Natural logarithm of ms2. *P < .05 nonsurvivors vs survivors.
older healthy individuals. Saul et all6 observed a significant inverse correlation between age and the frequency domain of heart rate variability in control subjects but not in patients with congestive heart failure.The frequency domain of heart rate variability was lower in patients with high plasma norepinephrine in the current study, but we also observed a significant age-related increase in plasma norepinephrine level.We cannot, therefore, exclude the possibility that age differences were responsible for the decreases in the power of frequency domains. However, there was no correlation between age and frequency domain in the current study, which suggests that the increase in the plasma norepinephrine level per se was related to the alteration in heart rate variability.
Baroreceptor sensitivity It is well known that baroreceptor-mediated control is attenuated in congestive heart failure. In human beings, Sopher et al13 used a ramped neck pressure-suction sequence to unload and stimulate carotid sinus baroreceptors, measuring heart rate at each step to calculate arterial baroreceptor reflex sensitivity.Arterial baroreceptor–heart rate reflex sensitivity was less in patients with heart failure than in normal subjects. Ferguson et al14 examined muscle sympathetic nerve activity during perturbation of blood pressure by using phenylephrine and nitroprusside in patients with moderate to severe congestive heart failure and found that baroreflex response during nitroprusside-induced
baroreceptor deactivation was strikingly attenuated but sympathoinhibitory response to pressor stimulus was not in patients with heart failure. Baroreceptor sensitivity was correlated with plasma atrial natriuretic peptide level but not with plasma norepinephrine.There was a significant correlation between baroreceptor sensitivity and the low-frequency power. There was no correlation between baroreceptor sensitivity and high-frequency power, which reflects parasympathetic nervous activity,25,26 although baroreceptor sensitivity during increase in blood pressure may reflect vagal afferent pathway.27 These results are difficult to interpret. Some studies have suggested that plasma atrial natriuretic peptide level affects baroreceptor sensitivity.28,29 Volpe et al28 found that the increase in baroreceptor sensitivity induced by atrial natriuretic peptide was abolished by administration of an ACE inhibitor.They speculated that the effect of atrial natriuretic peptide was mediated by inhibition of angiotensin II, which affects baroreceptor sensitivity.Woods et al29 found that atrial natriuretic peptide affected baroreceptor sensitivity when assessed by the ramp method but not by the steady-state method and suggested that atrial natriuretic peptide preferentially affects a nonarterial baroreceptor component, such as the cardiopulmonary reflex.The close correlation observed between plasma atrial natriuretic peptide level and baroreceptor sensitivity in the current study supports these findings.An increase in atrial natriuretic peptide may be one of the compensatory mechanisms for the attenuated baroreceptor sensitivity in patients with congestive heart failure. Like the frequency domains of heart rate variability, baroreceptor sensitivity may also be affected by aging.30 Again, there was no correlation between age and baroreceptor sensitivity in the current study.Thus increases in neurohumoral factors appeared to be related to the decrease in baroreceptor sensitivity.The baroreceptor–heart rate sensitivity that we assessed may be affected by a number of other factors, such as nonarterial baroreflex components and end-organ responsiveness.Assessment of the pure carotid sinus baroreflex with the use of a neck chamber or direct recording of sympathetic nerve activity would be needed to exclude the influence of these factors.
Heart rate variability and baroreceptor sensitivity as indexes of autonomic regulation in congestive heart failure In this study, heart rate variability reflected plasma norepinephrine and renin levels, whereas baroreceptor sensitivity independently reflected atrial natriuretic peptide level.Although cardiac function was correlated with some neurohumoral factors, it was not correlated with heart rate variability or baroreceptor sensitivity. These findings are consistent with the results of a previous study, which showed that none of the measures of
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heart rate variability was correlated with left ventricular ejection fraction, cardiac output, or functional classification.17 The low-frequency power was correlated with baroreceptor sensitivity in this study. In this regard, these measures reflecting autonomic regulation independently could be prognostic indicators different from other conventional clinical variables in patients with congestive heart failure. We thank the following investigators who participated in the study: Keiichi Nagami, MD, Keiyu Hospital, Yokohama; Michiyo Hosokawa, MD, and Hitoshi Yokozuka, MD, Urawa Municipal Hospital, Urawa; Tomomi Meguro, MD, Mito Red Cross Hospital, Mito; and Natsuki Kobayashi, MD, Saitama Central Hospital, Urawa.
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